Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use

ABSTRACT

The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: 
                         
wherein variables A 1 , A 3 , A 4 , A 5 , A 6 , A 8 , L, R 2 , R 7 , R 9 , W and Y of Formula I are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to plaque formation and deposition, resulting from the activity of BACE. Such BACE mediated disorders include, for example, Alzheimer&#39;s Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas II and III, sub-Formula embodiments of Formulas I, II and III, intermediates and processes and methods useful for the preparation of compounds of Formulae I-III.

RELATED APPLICATIONS

This application is a U.S. national stage application under 35 U.S.C.§371 of International Application No. PCT/US2011/061473, having aninternational filing date of Nov. 18, 2011, which claims the benefit of,and priority to, U.S. Provisional Application No. 61/416,718, filed onNov. 23, 2010, each specification of which is hereby incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The invention relates generally to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treatbeta-secretase mediated diseases and conditions, including, withoutlimitation, Alzheimer's disease, plaque formation and related centralnervous system (CNS) disorders.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) affects greater than 12 million aging peopleworldwide, and importantly, the number affected continues to grow. ADaccounts for the majority of dementia clinically diagnosed after the ageof 60. AD is generally characterized by the progressive decline ofmemory, reasoning, judgement and orientation. As the disease progresses,motor, sensory, and vocal abilities are affected until there is globalimpairment of multiple cognitive functions. The loss of cognitivefunction occurs gradually, typically leading to a diminished cognitionof self, family and friends. Patients with severe cognitive impairmentand/or diagnosed as end-stage AD are generally bedridden, incontinent,and dependent on custodial care. The AD patient eventually dies in aboutnine to ten years, on average, after initial diagnosis. Due to theincapacitating, generally humiliating and ultimately fatal effects ofAD, there is a need to effectively treat AD upon diagnosis.

AD is characterized by two major physiological changes in the brain. Thefirst change, beta amyloid plaque formation, supports the “amyloidcascade hypothesis” which conveys the thought that AD is caused by theformation of characteristic beta amyloid peptide (A-beta), or A-betafragments thereof, deposits in the brain (commonly referred to as betaamyloid “plaques” or “plaque deposits”) and in cerebral blood vessels(beta amyloid angiopathy). A wealth of evidence suggests thatbeta-amyloid and accompanying amyloid plaque formation is central to thepathophysiology of AD and is likely to play an early role in thisintractable neurodegenerative disorder. The second change in AD is theformation of intraneuronal tangles, consisting of an aggregate form ofthe protein tau. Besides being found in patients with AD, intraneuronaltangles are also found in other dementia-inducing disorders. Joachim etal., Alz. Dis. Assoc. Dis., 6:7-34 (1992).

Several lines of evidence indicate that progressive cerebral depositionof A-beta plays a seminal role in the pathogenisis of AD and can precedecognitive symptoms by years or even decades. Selkoe, Neuron, 6:487(1991). Release of A-beta from neuronal cells grown in culture and thepresence of A-beta in cerebrospinal fluid (CSF) of both normalindividuals and AD patients has been demonstrated. Seubert et al.,Nature, 359:325-327 (1992). Autopsies of AD patients have revealed largenumbers of lesions comprising these 2 factors in areas of the humanbrain believed to be important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloid containing plaques and vascular amyloid angiopathywere also found in the brains of individuals with Down's Syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type(HCHWA-D), and other neurodegenerative disorders.

It has been hypothesized that A-beta formation is a causative precursoror factor in the development of AD. More specifically, deposition ofA-beta in areas of the brain responsible for cognitive factors isbelieved to be a major factor in the development of AD. Beta amyloidplaques are primarily composed of amyloid beta peptide (A-beta peptide).A-beta peptide is derived from the proteolytic cleavage of a largetransmembrane amyloid precursor protein (APP), and is a peptide rangingin about 39-42 amino acid residues. A-beta 42 (42 amino acids long) isthought to be the major component of these plaque deposits in the brainsof Alzheimer's Disease patients. Citron, Trends in PharmacologicalSciences, 25(2):92-97 (2004).

Similar plaques appear in some variants of Lewy body dementia and ininclusion body myositis, a muscle disease. A β also forms aggregatescoating cerebral blood vessels in cerebral amyloid angiopathy. Theseplaques are composed of a tangle of regularly ordered fibrillaraggregates called amyloid fibers, a protein fold shared by otherpeptides such as prions associated with protein misfolding diseases.Research on laboratory rats suggest that the two-molecule, soluble formof the peptide is a causative agent in the development of Alzheimer'sand that the two-molecule form is the smallest synaptotoxic species ofsoluble amyloid beta oligomer. Shankar, G. M., Nature Medicine (Jun. 22,2008) online doi 10:1038 nm 1782.

Several aspartyl proteases, including beta-secretase andgamma-secretase, are thought to be involved in the processing orcleavage of APP, resulting in the formation of A-beta peptide. Betasecretase (BACE, also commonly referred to as memapsin) is thought tofirst cleave APP to generate two fragments: (1) a first N-terminusfragment (beta APP) and (2) a second C-99 fragment, which issubsequently cleaved by gamma secretase to generate the A-beta peptide.APP has also found to be cleaved by alpha-secretase to producealpha-sAPP, a secreted form of APP that does not result in beta-amyloidplaque formation. This alternate pathway precludes the formation ofA-beta peptide. A description of the proteolytic processing fragments ofAPP is found, for example, in U.S. Pat. Nos. 5,441,870, 5,712,130 and5,942,400.

BACE is an aspartyl protease enzyme comprising 501 amino acids andresponsible for processing APP at the beta-secretase specific cleavagesite. BACE is present in two forms, BACE 1 and BACE 2, designated assuch depending upon the specific cleavage site of APP. Beta secretase isdescribed in Sinha et al., Nature, 402:537-554 (1999) (p510) and PCTapplication WO 2000/17369. It has been proposed that A-beta peptideaccumulates as a result of APP processing by BACE. Moreover, in vivoprocessing of APP at the beta secretase cleavage site is thought to be arate-limiting step in A-beta production. Sabbagh, M. et al., Alz. Dis.Rev. 3:1-19 (1997). Thus, inhibition of the BACE enzyme activity isdesirable for the treatment of AD.

Studies have shown that the inhibition of BACE may be linked to thetreatment of AD. The BACE enzyme is essential for the generation ofbeta-amyloid or A-beta. BACE knockout mice do not produce beta-amyloidand are free from Alzheimer's associated pathologies including neuronalloss and certain memory deficits. Cole, S. L., Vasser, R., MolecularDegeneration 2:22, 2007. When crossed with transgenic mice that overexpress APP, the progeny of BACE deficient mice show reduced amounts ofA-beta in brain extracts as compares with control animals (Luo et al.,Nature Neuroscience, 4:231-232 (2001)). The fact that BACE initiates theformation of beta-amyloid, and the observation that BACE levels areelevated in this disease provide direct and compelling reasons todevelop therapies directed at BACE inhibition thus reducing beta-amyloidand its associated toxicities. To this end, inhibition of beta secretaseactivity and a corresponding reduction of A-beta in the brain shouldprovide a therapeutic method for treating AD and other beta amyloid orplaque related disorders.

Consequently, the approach of regulating or reducing the formation ofA-beta peptide formation and deposition as a potential treatment for ADhas received tremendous attention and belief from both researchers andinvestors alike. A small molecule gamma-secretase inhibitor, LY450139(“Semagacestat”), an A-beta lowering agent, is in phase II and Phase IIIclinical trials for the treatment of Alzheimer's Disease. Thepharmacokinetics of semagacestat in plasma, as well as the plasma andcerebral spinal fluid (CSF) A-Beta peptide levels as pharmacodynamicresponses to semagacestat administration were evaluated in healthy humansubjects in single and multiple doses, and pharmacokinetic andpharmacodynamic changes were also assessed in mild to moderate ADpatients in two (2) clinical trials (Expert Opin. Pharmacother. (2009),10 (10); Clin. Neuropharmacol. 2007; 30 (pgs 317-325); and Neurology,2006, 66 (pgs 602-624)).

Additional approaches have been taken in attempts to treat AD andplaque-related disorders. One such approach to reduce the formation ofplaque on the brain involves the inhibition of and, therefore, thereduction of BACE activity. For example, each of the following PCTpublications: WO 07/058,602, WO 10/021,680, WO 10/105,179, WO 06/041404,WO 07/114,771, WO 08/076,045, WO 08/076,046, WO 08/150,217, WO07/038,271, WO 09/091,016, WO 08/108,378, WO 09/134,617, WO 05/097767,WO 08/092,785, WO 06/138265, WO 08/103,351, WO 06/138230, WO 08/200,445,WO 06/111370, WO 07/287,692, WO 05/058311, EP 01942105, WO 08/133,273,WO 08/133,274, WO 07/049,532, US20070027199, WO 07/038,271,US20070072925, US20070203116, WO 08/118,379, WO 06/076284,US20070004786, WO 06/083760, WO 07/011,810, WO 07/011,833, WO07/100,536,WO 08/054,698, WO10/128,058, WO10/030,945 and WO11/130,741, describeinhibitors of BACE, useful for treating AD and other beta-secretasemediated disorders.

The lysosomal aspartic protease Cathepsin D (CatD) is ubiquitouslyexpressed in eukaryotic organisms. CatD activity is essential toaccomplish the acid-dependent extensive or partial proteolysis ofprotein substrates within endosomal and lysosomal compartments thereindelivered via endocytosis, phagocytosis or autophagocytosis. CatD mayalso act at physiological pH on small-size substrates in the cytosol andin the extracellular milieu. Mouse and fruit fly CatD knock-out modelshave highlighted the multi-pathophysiological roles of CatD in tissuehomeostasis and organ development.

Inhibition of protein Cathepsin D has been implicated in undesirableside effects. For instance, the inhibition of Cathepsin D is believed tobe linked to adverse retinal development and retinal atrophy.Particularly, in mice it was found that cathepsin D is essential for themetabolic maintenance of retinal photoreceptor cells and that itsdeficiency induces apoptosis of the cells, while the loss of INL neuronsis mediated by NO from microglial cells. However, in the very same mice,it was also found that no atrophic change was detected in the retina ofmice deficient in cathepsin B or L. Mol. Cell. Neurosci, 2003, February22(2):146-161. Further, Animal models of cathepsin D (CatD) deficiencyare characterized by a progressive and relentless neurodegenerativephenotype similar to that observed in Neuronal Ceroid Lipofuscinoses(NCL), a group of pediatric neurodegenerative diseases knowncollectively as Batten Disease. It has been shown that the targeteddeletion of the pro-apoptotic molecule Bax prevents apoptotic markersbut not neuron death and neurodegeneration induced by CatD deficiency,which suggests that alterations in the macroautophagy-lysosomaldegradation pathway can mediate neuron death in NCL/Batten Disease inthe absence of apoptosis. Autophagy, 2007, September-October;3(5):474-476. Finally, an adverse effect of the inhibition of Cat D isevident from the data presented in PLoS One, 2011; 6(7):e21908,published Jul. 1, 2011. The authors of the PLoS One paper found thatknock-down of cathepsin D affects the retinal pigment epithelium,impairs swim-bladder ontogenesis and causes premature death inzebrafish. The main phenotypic alterations produced by CatD knock-downin zebrafish were: 1. abnormal development of the eye and of retinalpigment epithelium; 2. absence of the swim-bladder; 3. skinhyper-pigmentation; 4. reduced growth and premature death. Rescueexperiments confirmed the involvement of CatD in the developmentalprocesses leading to these phenotypic alterations.

Moreover, such toxicity findings thought to be related to the inhibitionof CatD has played a role in the termination of a human Bace-mediatedAlzheimer's Disease clinical trial. Eli Lilly terminated a phase Iclinical trial of LY 2811376 after rat toxicology studies showed that ahigher compound dose given for three months ravaged the pigmentepithelium of the rat's eye. The retinal layer had inclusions andextensive damage. Lilly ended the Ph I dosing and brought people in foreye assessments, which did not show any abnormalities (Alzheimer'sResearch Forum News, Mar. 31, 2011 reporting on Martin Citron'spresentation at the AD/PD Conference March 2011 in Barcelona, Spain)

Hence, it is desirable to provide compounds which modulate the activityof BACE while not suffering from the undesirable retinal side effectspossibly due to intervention in the CatD pathway or due to the reductionand/or direct inhibition of the cathepsin D protein.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful for themodulation of beta secretase activity, and as treatment of AD.Particularly, the compounds of the invention are useful for theregulation or reduction of the formation of A-beta peptide and,consequently, the regulation and/or reduction of formation of betaamyloid plaque both on the brain, as well as in the CNS. To this end,the compounds are useful for the treatment of AD and other betasecretase and/or plaque-related and/or mediated disorders. For example,the compounds are useful for the prophylaxis and/or treatment, acuteand/or chronic, of AD and other diseases or conditions involving thedeposition or accumulation of beta amyloid peptide, and formation ofplaque, on the brain.

The compounds provided by the invention, including stereoisomers,tautomers, hydrates, solvates and pharmaceutically acceptable saltsthereof, are generally defined by Formula I

wherein each of A¹, A³, A⁴, A⁵, A⁶, L, R², R⁷, R⁹, W and Y of Formula Iare defined below. The invention also provides procedures for makingcompounds of Formula I, and sub-Formulas thereof, as well asintermediates useful in such procedures.

The invention further provides pharmaceutical compositions comprisingcompounds of the invention, and uses of the compounds and compositionsof the invention in the treatment of beta secretase mediated diseases.For example, and in one embodiment, the invention provides apharmaceutical composition comprising an effective dosage amount of acompound of Formula I in association with at least one pharmaceuticallyacceptable excipient.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, there are provided compounds,including stereoisomers, tautomers, hydrates, solvates andpharmaceutically acceptable salts thereof, which are generally definedby Formula I:

wherein A¹ is CR¹ or N;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵ or N;

A⁶ is CR⁶ or N;

A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

L is absent or L is —C(═O)NH—, C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,C₃₋₆cycloalkyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza[3,5]-spironon-7-yl andC₃₋₆cycloalkyl are optionally substituted, independently, with 1-5substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —SC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza[3,5]-spironon-7-yl, cyclopentylor cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl,—NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R¹⁰;

R⁹ is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portionof —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkylare optionally substituted with 1-3 substituents of F, oxo or OH;

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl;

W is absent, CH₂ or CF₂; and

Y is —C(═O)— or —SO₂—.

In one embodiment of the invention, there are provided compounds,including stereoisomers, tautomers, hydrates, solvates andpharmaceutically acceptable salts thereof, which are generally definedby Formula I-A:

wherein

A¹ is CR¹ or N;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵ or N;

A⁶ is CR⁶ or N;

A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza[3,5]-spironon-7-yl, cyclopentyland cyclohexyl are optionally substituted, independently, with 1-5substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza[3,5]-spironon-7-yl, cyclopentylor cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl,—NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R¹⁰;

R⁹ is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portionof —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkylare optionally substituted with 1-3 substituents of F, oxo or OH;

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl; and

W is absent or CH₂.

In one embodiment of the invention, there are provided compounds,including stereoisomers, tautomers, hydrates, solvates andpharmaceutically acceptable salts thereof, which are generally definedby Formula I-B:

wherein

A¹ is CR¹ or N;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵ or N;

A⁶ is CR⁶ or N;

A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰;

R⁹ is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portionof —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkylare optionally substituted with 1-3 substituents of F, oxo or OH;

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl; and

W is absent or CH₂.

In another embodiment, the invention includes compounds wherein W isabsent, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein W is CH₂or CF₂, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein W isCF₂, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein W isCH₂, in conjunction with any of the above or below embodiments.

In another embodiment of the present invention, the compounds, andsolvates, tautomers, hydrates, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formulas I or I-A, wherein

A¹ is CH or CF;

A³ is CH, CF or N;

A⁴ is CH, CF or N;

A⁵ is CH;

A⁶ is CH;

A⁸ is CH;

L is absent (Formula I-A) or L is —C(═O)NH—, C(═O)N(CH₃)—, —NH— or—N(CH₃)— (Formula I);

R² is C₃₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₄alkynyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,dihydropyranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,morpholinyl or 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, wherein theC₃₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyranyl,tetrahydropyranyl, pyrrolidinyl, morpholinyl and8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, are optionally substituted,independently, with 1-5 substituents of R¹⁰;

R⁷ is C₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl orpyridazinyl, wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl,pyrazinyl and pyridazinyl are optionally substituted, independently,with 1-3 substituents of R¹⁰;

R⁹ is CH₃, C₂H₅, propyl, butyl, acetyl or benzyl;

each R¹⁰, independently, is F, Cl, CF₃, CN, CH₃, —OCH₃, —SCH₃, —NHCH₃,oxetanyl or C₂₋₃alkynyl; and

W is absent or CH₂.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II

wherein

A¹ is CR¹ or N;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵ or N;

A⁶ is CR⁶ or N;

A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

L is absent or L is —C(═O)NH—, —C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,C₃₋₆cycloalkyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl, andC₃₋₆cycloalkyl are optionally substituted, independently, with 1-5substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰;

R⁹ is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portionof —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkylare optionally substituted with 1-3 substituents of F, oxo or OH; and

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl; and

Y is —C(═O)— or —SO₂—.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II-A

wherein

A¹ is CR¹ or N;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵ or N;

A⁶ is CR⁶ or N;

A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰;

R⁹ is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portionof —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkylare optionally substituted with 1-3 substituents of F, oxo or OH; and

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II-B

wherein

A³ is CR³ or N;

A⁴ is CR⁴ or N; provided no more than one of A³ and A⁴ is N;

A⁶ is CR⁶ or N;

L is —C(═O)NH— or C(═O)N(CH₃)—;

each of R³, R⁴, R⁵, R⁶ and R⁸, independently, is H, F, Cl, Br, CF₃,OCF₃, CH₃, C₂H₅, CN, OH, OCH₃;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃)₃, whereinthe C₁₋₆-alkyl, C₂₋₂₄alkenyl, C₂₋₂₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl andC₃₋₆cycloalkyl are optionally substituted, independently, with 1-5substituents of R¹⁰;

each of R³ and R⁶, independently, is H, F, Cl, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH or OC₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl or cyclohexyl, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃ alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl andcyclohexyl are optionally substituted, independently, with 1-3substituents of R¹⁰;

R⁹ is H, CH₃, C₂H₅, propyl, butyl, acetyl or benzyl; and

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,piperazinyl, oxetanyl or dioxolyl, wherein each of the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkylamino-,C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, morpholinyl, pyrazolyl,isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, isoptionally substituted independently with 1-5 substituents of F, Cl, CN,NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃dialkylamino, C₁₋₃thioalkoxyl, or oxetanyl.

In another embodiment of the present invention, the compounds, andsolvates, tautomers, stereoisomers and pharmaceutically acceptable saltsthereof, are defined by Formula II-C

wherein each of A³, A⁴, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is as definedabove with respect to either Formula I, Formula II-A or Formula II-B.

Formula II, and sub-formulas A, B and C thereof, illustrate embodimentsof Formula I wherein W is absent.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formulas I, II, II-A, II-B orII-C wherein

A³ is CR³ or N;

A⁴ is CR⁴;

R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ringare optionally substituted, independently, with 1-3 substituents of R¹⁰;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;

each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thienyl, said ring optionally substituted,independently, with 1-3 substituents of R¹⁰; and

R⁹ is CH₃.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula III

wherein

A¹ is CR¹ or N;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵ or N;

A⁶ is CR⁶ or N;

A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

L is absent or L is —C(═O)NH—, C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃)₃, whereinthe C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl, andC₃₋₆cycloalkyl are optionally substituted, independently, with 1-5substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰;

R⁹ is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portionof —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkylare optionally substituted with 1-3 substituents of F, oxo or OH; and

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula III-A

wherein

A¹ is CR¹ or N;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵ or N;

A⁶ is CR⁶ or N;

A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰;

R⁹ is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portionof —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkylare optionally substituted with 1-3 substituents of F, oxo or OH; and

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula III-B

wherein

A³ is CR³ or N;

A⁴ is CR⁴ or N; provided no more than one of A³ and A⁴ is N;

A⁶ is CR⁶ or N;

each of R¹, R³, R⁴, R⁵, R⁶ and R⁸, independently, is H, F, Cl, Br, CF₃,OCF₃, CH₃, C₂H₅, CN, OH, OCH₃;

L is absent or L is —C(═O)NH—, C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclohexyl or —Si(CH₃)₃, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl andcyclohexyl are optionally substituted, independently, with 1-5substituents of R¹⁰;

each of R³ and R⁶, independently, is H, F, Cl, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH or OC₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl or cyclohexyl, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl andcyclohexyl are optionally substituted, independently, with 1-3substituents of R¹⁰;

R⁹ is H, CH₃, C₂H₅, propyl, butyl, acetyl or benzyl; and

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,piperazinyl, oxetanyl or dioxolyl, wherein each of the C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkylamino-,C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, morpholinyl, pyrazolyl,isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, isoptionally substituted independently with 1-5 substituents of F, Cl, CN,NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃dialkylamino, C₁₋₃thioalkoxyl, or oxetanyl.

In another embodiment of the present invention, the compounds, andsolvates, tautomers, stereoisomers and pharmaceutically acceptable saltsthereof, are defined by Formula III-C

wherein each of A³, A⁴, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is asdefined above with respect to Formula I, Formula III-A or Formula III-B.

-   -   For Example, and in another embodiment of the present invention,        the compounds, and solvates, tautomers, stereoisomers and        pharmaceutically acceptable salts thereof, are defined by        Formula III-C wherein

A³ is CR³ or N;

A⁴ is CR⁴;

L is —C(═O)NH—;

R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ringare optionally substituted, independently, with 1-3 substituents of R¹⁰;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;

each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thienyl, said ring optionally substituted,independently, with 1-3 substituents of R¹⁰;

R⁹ is CH₃; and

each R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl.

The present invention contemplates that the various differentembodiments of Formulas I, II and III, and sub-Formulas A, B and Cthereof, described herein, may comprise the following embodiments withrespect to individual variables of A¹, A³, A⁴, A⁵, A⁶, A⁸, R², R⁷, and Wwhere applicable, as described below. Hence, these embodiments withrespect to individual variables A¹, A³, A⁴, A⁵, A⁶, A⁸, R², R⁷, and Wwhere applicable, may be applied “in conjunction with any of the other{above and below} embodiments” to create various embodiments of generalFormulas I, II and III and each sub-formula thereof, which are notliterally described herein.

In another embodiment, the invention includes compounds wherein A¹ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ is CHor N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ isCF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ is CFor N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ is CHor N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ isCF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁵ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁵ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁵ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁶ isCR⁶ wherein R⁶ is H, F, Br or

or A⁶ is N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁶ isCH, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁶ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁸ isCR⁸ wherein R⁸ is F, Br or

in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁸ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁸ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁸ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹ or N, A³ is CR³ or N, A⁴ is CR⁴ or N, A⁵ is CR⁵ or N, A⁶ is CR⁶ or Nand A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶and A⁸ is N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is CR³ or N, A⁴ is CR⁴ or N, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸,provided that no more than one of A³ and A⁴ is N, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is N, A⁴ is CR⁴, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is CR³, A⁴ is N, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is CR³ or N, A⁴ is CR⁴ or N, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸,wherein each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃,OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkylportion of —OC₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH and each ofR³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl, provided that no more than one of A³ and A⁴ is N, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ is CHor CF, A³ is CH, CF or N, A⁴ is CH, CF or N, A⁵ is CH, CF or N, A⁶ isCH, CF or N, A⁸ is CH or CF, and R⁹ is H, CH₃, C₂H₅, propyl, butyl,acetyl or benzyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein L isabsent or L is —C(═O)NH—, —C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L isabsent, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L is—C(═O)NH—, —C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—, in conjunction with anyof the above or below embodiments.

In another embodiment, the invention includes compounds wherein L is—C(═O)NH—, —NH— or —O—, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein L is—C(═O)NH— or —NH—, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein L is—C(═O)NH—, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein L is—NH—, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R¹ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isCl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃)₃, whereinthe C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl and C₃₋₆cycloalkyl are optionallysubstituted, independently, with 1-5 substituents of R¹⁰, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃)₃, whereinthe C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl and C₃₋₆cycloalkyl are optionallysubstituted, independently, with 1-3 substituents of R¹⁰, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isC₃₋₆-alkyl, C₃₋₈-cycloalkyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyranyl,tetrahydropyranyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,morpholinyl or 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, wherein theC₃₋₆-alkyl, C₃₋₈-cycloalkyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyranyl,tetrahydropyranyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,morpholinyl and 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl are optionallysubstituted, independently, with 1-3 substituents of R¹⁰, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isC₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl, dihydropyranyl,tetrahydropyranyl, pyrrolidinyl, tetrahydropyrroly or piperidinyl,wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl,dihydropyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydropyrroly andpiperidinyl are optionally substituted, independently, with 1-3substituents of R¹⁰, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R² isC₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, dihydropyranyl, pyrrolidinyl,tetrahydropyrrolyl or piperidinyl, wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl,pyridyl, dihydropyranyl, pyrrolidinyl, tetrahydropyrrolyl andpiperidinyl are optionally substituted, independently, with 1-3substituents of R¹⁰, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R² isC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl or —NH-benzyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl and —NH-benzyl are optionallysubstituted, independently, with 1-3 substituents of R¹⁰, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² ishalo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or aring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R¹⁰, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R³ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁴ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁴ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁴ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁴ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁴ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁵ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁵ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁵ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁵ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁵ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁶ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isCl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R¹⁰, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isphenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-3 substituents of R¹⁰, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isC₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl orpyridazinyl, wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl,pyrazinyl and pyridazinyl are optionally substituted, independently,with 1-3 substituents of R¹⁰, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isC₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, 3-pyridyl, 5-pyrimidyl, pyrazinyl or2-pyridazinyl, wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, 3-pyridyl,5-pyrimidyl, pyrazinyl and 2-pyridazinyl are optionally substituted,independently, with 1-3 substituents of R¹⁰, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ is aring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, said ringoptionally substituted, independently, with 1-3 substituents of R¹⁰, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ is aring selected from phenyl, 3-pyridyl, 5-pyrimidyl, 2-pyrazinyl or2-pyridazinyl, said ring optionally substituted, independently, with 1-5substituents of R¹⁰, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁷ isphenyl, 3-pyridyl, 5-pyrimidyl, 2-pyrazinyl or 2-pyridazinyl, each ofwhich is optionally substituted with 1-5 substituents of F, Cl, Br, I,CN, CF₃, C₂F₅, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,SC₁₋₆-alkyl, oxetanyl or C₂₋₃alkynyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁸ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein each R¹,R⁴, R⁵ and R⁸, independently, is F, Cl, CF₃, OCF₃, methyl, CN, OH, OCH₃,SCH₃, NHCH₃, oxetanyl or C₂₋₃alkynyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention includes compounds wherein each R⁹,independently, is F, methyl, CN, OH, oxetanyl or C₂₋₃alkynyl, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁹ is H,C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl orbenzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁹ is F,CF₃, CN, CH₃, —OCH₃, —SCH₃, —NHCH₃, oxetanyl or C₂₋₃alkynyl, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁹ is H,CH₃, C₂H₅, propyl, butyl, acetyl or benzyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁹ is H,CH₃, or benzyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁹ isCH₃, C₂H₅, propyl, butyl, acetyl or benzyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁹ isCH₃, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein eachR¹⁰, independently, is F, Cl, CF₃, CN, CH₃, —OCH₃, —SCH₃, —NHCH₃,oxetanyl or C₂₋₃alkynyl, in conjunction with any of the above or belowembodiments.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula I, wherein

A¹ is CH or CF;

A³ is CH, CF or N;

A⁴ is CH, CF or N;

A⁵ is CH, CF or N;

A⁶ is CH, CF or N;

A⁸ is CH or CF; and

R⁹ is CH₃, C₂H₅, propyl, butyl, acetyl or benzyl.

In another embodiment of the present invention, the compounds, andsolvates, tautomers, stereoisomers and pharmaceutically acceptable saltsthereof, are defined by Formula I, I-A, II, II-A, II-B, III, III-A orIII-B, wherein

A¹ is CR¹;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵;

A⁶ is CR⁶;

A⁸ is CR⁸;

L is —C(═O)NH—, C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, CF₃, OCF₃,methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃;

one of R² and R⁷, independently, is phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃)₃, whereinthe phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl andC₃₋₆cycloalkyl are optionally substituted, independently, with 1-3substituents of R¹⁰;

the other of R² and R⁷, independently, is C₁₋₆-alkyl, C₃₋₆cycloalkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl or —NH-benzyl, wherein the C₁₋₆-alkyl,C₃₋₆cycloalkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl and —NH-benzyl are optionallysubstituted, independently, with 1-3 substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, SC₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl; and

R⁹ is CH₃ or benzyl.

In another embodiment of the present invention, the compounds, andsolvates, tautomers, stereoisomers and pharmaceutically acceptable saltsthereof, are defined by Formula I, I-A, II, II-A, II-B, III, III-A orIII-B, wherein

A¹ is CH or CF;

A³ is CH, CF or N;

A⁴ is CH, CF or N;

A⁵ is CH, CF or N;

A⁶ is CH, CF or N;

A⁸ is CH or CF, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

L is —C(═O)NH—;

R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cycloproyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ringare optionally substituted, independently, with 1-5 substituents of R¹⁰;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;

each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thienyl, said ring optionally substituted,independently, with 1-3 substituents of R¹⁰;

R⁹ is CH₃;

each R¹⁰, independently, is F, Cl, Br, CH₃, CF₃, OH, NO₂, —NHCH₃, —OCH₃,—OCF₃, —SCH₃ or CN; and

W is absent or CH₂.

In another embodiment of the present invention, the compounds, andsolvates, tautomers, stereoisomers and pharmaceutically acceptable saltsthereof, are defined by Formula I, I-A, II, II-A, II-B, III, III-A orIII-B, wherein

A¹ is CH or CF;

A³ is N;

A⁴ is CH or CF;

A⁵ is CH or CF;

A⁶ is CH or CF;

A⁸ is CH;

R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₃₋₈-cycloalkyl, OR¹⁰, SR¹⁰ or a ring of phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₈-cycloalkyl andring are optionally substituted, independently, with 1-5 substituents ofR¹⁰;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thiophenyl, said ring optionally substituted,independently, with 1-3 substituents of R¹⁰;

R⁹ is CH₃;

each R¹⁰, independently, is H, F, Cl, Br, CH₃, CF₃, OH, NO₂, —NHCH₃,—OCH₃, —OCF₃, —SCH₃ or CN; and

W is absent or CH₂.

In another embodiment, the invention provides one or more of thecompounds, or a pharmaceutically acceptable salt thereof, of Formulas I,II and III, as taught and described herein.

In another embodiment, the invention provides the compound of Formula I,II or II-A, or a stereoisomer or pharmaceutically acceptable saltthereof, selected from

-   (4R)-2-amino-2′-methoxy-1-methyl-7′-(5-pyrimidinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one,    (4S)-2-amino-2′-methoxy-1-methyl-7′-(5-pyrimidinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoro-3-pyridinyl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4S)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoro-3-pyridinyl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-4′-fluoro-7′-methoxy-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4S)-2-amino-4′-fluoro-7′-methoxy-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4S)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4S)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4S)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4S)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4S)-2-amino-7′-(3-chlorophenyl)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-7′-(3-chlorophenyl)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4S)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;-   (4R)-2-amino-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-fluoro-4-pyridinyl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;    and-   (4S)-2-amino-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-fluoro-4-pyridinyl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;    and-   N-(2-amino-2′-methoxy-1-methyl-5-oxo-1,5-dihydrospiro[imidazole-4,9′-xanthen]-7′-yl)-5-chloropicolinamide.

In another embodiment, the invention provides the compound of Formula I,III, III-A, or a stereoisomer or pharmaceutically acceptable saltthereof, selected from

-   2′-amino-7-bromo-3-chloro-1-fluoro-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (R)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (R)-2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (R)-2′-amino-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-2′-amino-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   2′-amino-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (R)-2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-2′-amino-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   3,7-bis(2-fluoropyridin-3-yl)-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-7-bromo-3-chloro-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (R)-7-bromo-3-chloro-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   2′-amino-1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-2′-amino-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;-   (S)-2′-amino-3-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;    and-   (4′S)-2′-amino-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one.

All of the possible embodiments described herein for various of the Rgroups of the compounds of Formula I may be applied, as appropriate, tocompounds of Formulas II and III, and any sub-formulas thereof.

In another embodiment, the invention provides each of the Exemplarycompounds, and stereoisomers, tautomers, solvates, pharmaceuticallyacceptable salts, derivatives or prodrugs thereof, and relatedintermediates, described herein.

In another embodiment, the invention provides the exemplified compoundsdescribed herein, and pharmaceutically acceptable salt forms of eachthereof.

Definitions

The following definitions should assist in understanding the invention.

The term “comprising” is meant to be open ended, i.e., all encompassingand non-limiting. It may be used herein synonymously with “having.”Comprising is intended to include each and every indicated or recitedcomponent or element(s) while not excluding any other components orelements.

The terms “L is absent” and “W is absent” is intended to mean that thesevariables do not exist in the generic formula, i.e. they are merely abond connecting the two structural moieties as illustrated in theFormulas. For example, the compounds of Formula I wherein W is absentare compounds of Formula II, described herein. Similarly, the term “L isabsent” is intended to mean that variable R⁷ is attached directly to thecore of the compound, as illustrated, for instance, in Formulas I-A andII-A.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀; C₁-C₆; orC₁-C₄). Unless otherwise specified, one or more carbon atoms of the“alkyl” radical may be substituted, such as with a cycloalkyl moiety.Examples of “alkyl” radicals include methyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, ethyl, cyclopropylethyl,cyclobutylethyl, cyclopentylethyl, n-propyl, isopropyl, n-butyl,cyclopropylbutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,hexyl and the like.

The term “C_(α-β)alkenyl”, when used alone or in combination, embraceslinear or branched radicals having at least one carbon-carbon doublebond in a moiety having a number of carbon atoms in the range from α andβ. Included within alkenyl radicals are “lower alkenyl” radicals havingtwo to about six carbon atoms and, for example, those radicals havingtwo to about four carbon atoms. Examples of alkenyl radicals include,without limitation, ethenyl, propenyl, alkyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations, as appreciated by those of ordinary skill in theart.

The term “C_(α-β)alkynyl”, when used alone or in combination, denoteslinear or branched radicals having at least one carbon-carbon triplebond in a moiety having a number of carbon atoms in the range from α andβ. Examples of alkynyl radicals include “lower alkynyl” radicals havingtwo to about six carbon atoms and, for example, lower alkynyl radicalshaving two to about four carbon atoms. Examples of such radicalsinclude, without limitation, ethynyl, propynyl (propargyl), butynyl, andthe like.

The term “C_(α-β)-alkyl”, “C_(α-β)-alkenyl” and “C_(α-β)-alkynyl”, whenused with other terms such as “wherein 1, 2 or 3 carbon atoms of saidC_(α-β)-alkyl, C_(α-β)-alkenyl or C_(2α-β)-alkynyl is optionallyreplaced with a heteroatom selected from O, S, S(O), S(O)₂ and N”embraces linear or branched radicals wherein one or more of the carbonatoms may be replaced with a heteroatom. Examples of such “alkyl”radicals include —O-methyl, —O-ethyl, —CH₂—O—CH₃, —CH₂CH₂—O—CH₃,—NH—CH₂, —CH₂CH₂—N(CH₃)—CH₃, —S—(CH₂)₃CH₂, —CH₂CH₂—S—CH₃ and the like.Accordingly, such radicals also include radicals encompassed by —OR⁷where R⁷ may be defined as a C_(α-β)-alkyl. Examples of such “alkenyl”radicals include —NH—CH₂CH═CH₂, —S—CH₂CH₂CH═CHCH₃ and the like. Similarexamples exist for such “alkynyl” radicals, as appreciated by thoseskilled in the art.

The term “C_(α-β)alkoxyl” or “—OC_(α-β)alkyl” when used alone or incombination, embraces linear or branched oxygen-containing alkylradicals each having α to β number of carbon atoms (such as C₁-C₁₀). Theterms “alkoxy” and “alkoxyl”, when used alone or in combination,embraces linear or branched oxygen-containing radicals each having alkyland substituted alkyl portions of one or more carbon atoms. Examples ofsuch radicals include methoxy, ethoxy, propoxy, butoxy, tert-butoxy andneopentoxy. Alkoxy radicals may be further substituted with one or morehalo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy”radicals or with other substitution. Examples of such radicals includefluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” multi-ring system need not be aromatic, and the ring(s) fused tothe aromatic ring may be partially or fully unsaturated and include oneor more heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. The “aryl” group may be substituted, suchas with 1 to 5 substituents including lower alkyl, hydroxyl, halo,haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the like.Phenyl substituted with —O—CH₂—O— or —O—CH₂—CH₂—O— forms an arylbenzodioxolyl substituent.

The term “C_(α-β)-cycloalkyl”, also referred to herein as “carbocyclic”,when used alone or in combination, denotes a partially or fullysaturated ring radical having a number of carbon atoms in the range fromα and β. The “cycloalkyl” may contain one (“monocyclic”), two(“bicyclic”) or even three (“tricyclic”) rings wherein such rings may beattached together in a fused manner and each formed from carbon atoms.Examples of saturated carbocyclic radicals include saturated 3 to6-membered monocyclic groups such as cyclopropane, cyclobutane,cyclopentane and cyclohexane. Cycloalkyls may be substituted asdescribed herein.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 3-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that at least one, but not necessarily all, rings in abicyclic or tricyclic ring system is nonaromatic.

The terms “partially or fully saturated or unsaturated” and “saturatedor partially or fully unsaturated” with respect to each individual ring,refer to the ring either as fully aromatic (fully unsaturated),partially aromatic (or partially saturated) or fully saturated(containing no double or triple bonds therein). If not specified assuch, then it is contemplated that each ring (monocyclic) in a ringsystem (if bicyclic or tricyclic) may either be fully aromatic,partially aromatic or fully saturated, and optionally substituted withup to 5 substituents. This includes carbocyclics, heterocyclics, aryland heteroaryl rings.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of unsaturated heteroaryl radicals, include unsaturated 5- to6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms,including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The terms “heterocycle” or “heterocyclic”, when used alone or incombination, means a partially or fully saturated ring moiety containingone, two or even three rings wherein such rings may be attached togetherin a fused manner, formed from carbon atoms and including one or moreheteroatoms selected from N, O or S. Examples of saturated heterocyclicradicals include saturated 3 to 6-membered heteromonocyclic groupscontaining 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl,piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturatedheterocyclyl radicals include dihydrothienyl, dihydropyranyl,dihydrofuryl and dihydrothiazolyl.

The term “heterocycle” also embraces radicals where heterocyclicradicals are fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

Examples of partially saturated and fully saturated heterocyclylsinclude, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted” refers to a single ring of 3-, 4-, 5-, 6-, 7- or8-atom membered or a 6-, 7-, 8-, 9-, 10-, 11 or 12-atom memberedbicyclic ring system comprising the delineated number of atoms, theatoms being carbon or, where indicated, a heteroatom such as nitrogen(N), oxygen (O) or sulfur (S). Where the number of atoms is notdelineated, such as a “monocyclic ring system” or a “bicyclic ringsystem”, the numbers of atoms are 3-8 for a monocyclic and 6-12 for abicyclic ring. The ring or ring system may contain substitutentsthereon, attached at any atom that allows a stable compound to beformed. A bicyclic ring is intended to include fused ring systems aswell as spiro-fused rings. This phrase encompasses carbocyclics,heterocyclics, aryl and heteroaryl rings.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—. “Carbonyl” is also used hereinsynonymously with the term “oxo”.

The term “alkylthio” or “thioalkoxy” embraces radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” or “thioalkoxy” ismethylthio, (CH₃S—).

The groups —C(═O)NH— and —C(═O)N(CH₃)— in the defined scope of variable“L” is intended to include both orientations of the amido linker, ie.,C(═O)NH— and NHC(═O)— and C(═O)N(CH₃)— and N(CH₃) C(═O)—.

The term “Formula I” includes any sub formulas, such as Formulas II andIII. Similar with Formulas II and III, in that they include sub-formulaswhere described.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I-III is intended to refer to a form of thecompound that is safe for administration. For example, a salt form, asolvate, a hydrate, a prodrug or derivative form of a compound ofFormulas I-III, which has been approved for mammalian use, via oralingestion or other routes of administration, by a governing body orregulatory agency, such as the Food and Drug Administration (FDA) of theUnited States, is pharmaceutically acceptable.

Included in the compounds of Formulas I-III are the pharmaceuticallyacceptable salt forms of the free-base compounds. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. As appreciated by those of ordinary skill in the art, salts maybe formed from ionic associations, charge-charge interactions, covalentbonding, complexation, coordination, etc. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I-III may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoricacid. Appropriate organic acids may be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic andsulfonic classes of organic acids, examples of which include, withoutlimitation, formic, acetic, adipic, butyric, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formulas I-III include metallicsalts, such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases including,without limitation, primary, secondary and tertiary amines, substitutedamines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I-III.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66:1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative which is pharmaceutically acceptable.

The compound(s) of Formulas I-III may be used to treat a subject byadministering the compound(s) as a pharmaceutical composition. To thisend, the compound(s) can be combined with one or more excipients,including without limitation, carriers, diluents or adjuvants to form asuitable composition, which is described in more detail herein.

The term “excipient”, as used herein, denotes any pharmaceuticallyacceptable additive, carrier, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies. Accordingly, this term is not limited to a singledose, but may comprise multiple dosages required to bring about atherapeutic or prophylactic response in the subject. For example,“effective dosage amount” is not limited to a single capsule or tablet,but may include more than one capsule or tablet, which is the doseprescribed by a qualified physician or medical care giver to thesubject.

The term “leaving group” (also denoted as “LG”) generally refers togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I-III. The compounds of Formulas I-III can besynthesized according to the procedures described in the followingSchemes 1, 2, 3a, 3b, 4 and 5, wherein the substituents are as definedfor Formulas I-III above, except where further noted. The syntheticmethods described below are merely exemplary, and the compounds of theinvention may also be synthesized by alternate routes utilizingalternative synthetic strategies, as appreciated by persons of ordinaryskill in the art.

The following list of abbreviations used throughout the specificationrepresent the following and should assist in understanding theinvention:

-   ACN, MeCN—acetonitrile-   Aq., aq.—aqueous-   Ar—argon (gas)-   BOP—benzotriazol-1-yl-oxy Hexafluorophosphate-   BuLi—Butyllithium-   Cs₂CO₃—cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   Cu(1)I—copper(1) iodide-   DCC—dicyclohexylcarbodiimide-   DEA—diethylamine-   DIC—1,3-diisopropylcarbodiimide-   DIEA, DIPEA—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   DMSO—dimethylsulfoxide-   EDC, EDCI—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   G, gm—gram-   h, hr—hour-   H₂—hydrogen (gas)-   H₂O—water-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   HOAc—acetic acid-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   KI—potassium iodide-   LG—leaving group-   LDA—Lithium diisopropylamide-   LiOH—lithium hydroxide-   MgSO₄—magnesium sulfate-   MS—mass spectrum-   MeOH—methanol-   N₂—nitrogen (gas)-   NaCNBH₃—sodium cyanoborohydride-   Na₂CO₃—sodium carbonate-   NaHCO₃—sodium bicarbonate-   NaH—sodium hydride-   NaI—sodium iodide-   NaBH₄—sodium borohydride-   NaOH—sodium hydroxide-   Na₂SO₄—sodium sulfate-   NH₄Cl—ammonium chloride-   NH₄OH—ammonium hydroxide-   P(t-bu)₃—tri(tert-butyl)phosphine-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   Pd(dppf)C₁₂—palladium(1,1-bisdiphenylphosphinoferrocene) II chloride-   Pd(PhCN)₂Cl₂—palladium di-cyanophenyl dichloride-   Pd(OAc)₂—palladium acetate-   Pd₂(dba)₃—tris(dibenzylideneacetone)dipalladium-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT, rt—room temperature-   RBF, rbf—round bottom flask-   TLC, tlc—thin layer chromatography-   TBAF—Tetrabutylammonium flouride-   TBTU—O-benzotriazol-1-yl-N,N,N,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran-   UV—ultraviolet light

Scheme 1 describes an exemplary method for preparing racemic compounds 5of Formulas I and II, wherein W is absent. Beginning with compound 1,one of ordinary skill in the art may convert the methoxy group to thecorresponding hydroxyl via conventional O-demethylations techniques,such as use of BBr₃, as described herein, under suitable conditions, toafford compound 2. The alcohol-bromide 2 may be derivatized with desiredaromatic R⁷ groups using conventional Suzuki coupling methods viacoupling at the site of the bromide, or Suzuki-like aromatic-halogenexchange reactions, which reactions generally employ a boronic acidmoiety, a palladium catalyst reagent and a base. Other aryl/heteroarylcoupling methods, including Stille and the like under appropriateconditions, may also be employed to provide compounds 3. The hydroxylgroup of compound³ can be activated into a suitable leaving group (“LG”in scheme 1), such as a triflate, as described in the examples herein,or other suitable O-linked leaving group. The leaving group ofintermediate 4 can then be reacted with a desired aromatic boronic acidto install the desired R² group, as shown in scheme 1, to afford thedesired compounds 5 of Formula I and II.

Alternatively, the hydroxyl group of intermediate 2 may befunctionalized with the desired O-linked R² group via a base assistedcoupling reaction, as discussed herein, to provide the correspondingbromo-xanthene-R² intermediate (not shown). The bromide of thisintermediate may then be converted to the corresponding compounds 5using the conditions discussed above.

The boronic ester intermediates utilized in steps 2 and/or 4 may beprepared by methods described in the following references: (1) PCT Int.Patent Appl. No. WO 2005073189, titled “Preparation of fused heteroarylderivatives as p38 kinase inhibitors” or (2) PCT Int. Patent Appl. No.WO 2006094187, titled “Preparation of phthalazine, aza- anddiaza-phthalazine compounds as protein kinase, especially p38 kinase,inhibitors for treating inflammation and related conditions”. Also,desired boronic acids may be purchased commercially from vendorcatalogs, or specially made by the vendor or by persons of ordinaryskill in the art.

The Suzuki method is a reaction using a borane reagent, such as aboronic acid 7 or ester such as a dioxaborolane (see pages 82-84herein), and a suitable leaving group containing reagent, such as thexanthene 4 or bromo-xanthene 2 (halogens, including bromides andchlorides are suitable halogen leaving groups “LG”). As appreciated toone of ordinary skill in the art, Suzuki reactions also utilize apalladium catalyst. Suitable palladium catalysts include, withoutlimitation, Pd(PPh₃)₄, Pd(OAc)₂ or Pd(dppf)Cl₂. Where LG is a halide,the halide may be an iodide, a bromide or chloride. Chloro-pyridyl rings(where A¹=N) undergo Suzuki reactions in the presence of Pd catalysts.Other LGs are also suitable. For example, Suzuki couplings are known tooccur with a sulfonate, such as trifluoromethanesulfonate, as theleaving group.

The Suzuki reaction conditions may vary. For example, Suzuki reactionsare generally run in the presence of a suitable base such as a carbonatebase, bicarbonate or an acetate base, in a suitable solvent such astoluene, acetonitrile, DMF or an aqueous-organic solvent combination ora biphasic system of solvents. Further, the reaction may require heatdepending upon the particular bromide 2 and/or boronic acid or ester 7(see pgs 82-84), as appreciated by those skilled in the art. Inaddition, where the bromide is an aromatic moiety, such as phenyl, thereaction may be complete in a short period of time with heat.

Other coupling methods are known. For example metal catalized couplingchemistry, such Stille, Kumada, Negishi coupling methods, and the like,may be employed to the xanthene cores 2 and/or 4 to prepare desiredcyclic products 5. In addition, compounds may possess groups which mayneed to be protected (and later deprotected), such as a free aminogroup, to carry out effective coupling reactions to install either R² orR⁷ groups to afford the final desired compounds 5, as appreciated bypersons of ordinary skill in the art.

Desired compounds 7 of Formulas I, II and III, and sub-formulas thereof,wherein the R² group is —OR¹⁰ may be made as generally described inScheme 2. As shown, R⁷-hydroxy intermediate 6 can be functionalized asdesired, such as by alkylation as shown, by reaction with an alkylhalide 12 in the presence of a suitable base, such as cesium carbonate,in suitable solvents to afford the finally desired product 7.

“LG” in this instance is a “leaving group” which may be a halide such asan iodide, bromide, chloride or fluoride. LG may also be a non-halidemoiety such as an alkylsulfonate or other known groups which generallyform an electrophilic species (E⁺). Coupling reactions generally occurmore readily in one or a combination of solvents and a base. Suitablesolvents include, without limitation, generally non-nucleophilic,anhydrous solvents such as toluene, CH₂Cl₂, THF, DMF,N,N-dimethylacetamide and the like. The solvent may range in polarity,as appreciated by those skilled in the art. Suitable bases include, forexample, tertiary amine bases such as DIEA, TEA, carbonate bases such asNa₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH and the like, alkoxidessuch as NaOCH₃, and the like. The base itself may also serve as asolvent. These coupling reactions are generally fast and conversionoccurs typically in ambient conditions. However, depending upon theparticular substrate, such reactions may require heat, as appreciated bythose skilled in the art.

Desired compounds 12 of Formulas I and III where W is CH₂, andsub-Formulas thereof, may be prepared in a manner similar to thatdescribed in the Examples hereunder as shown in Scheme 3. Beginning withketone 6, one of ordinary skill in the art may convert the ketone groupto the corresponding spiro-dihydro-pyrimidinone-ylidine carbamate 9 viathe techniques described in Example 10. The BOC-protected amine group ofintermediate 9 may be deprotected by conventional methods, such as byacid (TFA for instance) to provide the free amino intermediate 10.Alternatively, compounds 9 may be functionalized at the desired R⁷and/or R² positions in Formulas I and III, using Suzuki or Suzuki-likeconditions as described herein, in scheme 1 and in the Examples, toafford protected compounds 12 (not shown), which then may be treatedwith a suitable acid, such as TFA to afford the acid salt (or free base)of compounds 12.

Intermediate 10 may successively be taken through Suzuki couplingreactions, or Suzuki-like aromatic-halogen exchange reactions includingStille and the like, under appropriate conditions, to provide finalcompounds 12.

Desired compounds 17 of Formulas I-III, and sub-formulas thereof whereinL is an amine or an amide linker to desired R⁷ groups may be made asgenerally described in Scheme 4. As shown, desired R⁷ amines may becoupled directed to the bromide intermediate 14 using XPhos in thepresence of a suitable palladium catalyst under suitable conditions toafford desired products 15.

Similarly, compound 14 can be transformed into the corresponding amine16 using conditions like those described in scheme 1 hereinabove.Compound 16 may then be reacted with a desired acid in the presence ofconventional amide coupling conditions to afford desired compound 17.Alternatively the R⁷-acid may be converted to the correspondingacid-halide, such as a reactive acid-chloride using oxalyl chlorideunder suitable conditions, and reacted with the amine 16 in the presenceof a suitable base and solvent to afford product 17.

EXAMPLES

The Examples, described herein below, represent various exemplarystarting materials, intermediates and compounds of Formulas I-III, whichshould assist in a better understanding and appreciation of the scope ofthe present invention and of the various methods which may be used tosynthesize compounds of Formulas I-III. Starting materials andintermediates used in the Examples herein may also be prepared using theprocedures described in co-pending U.S. patent application Ser. No.12/558,426, filed Sep. 11, 2009, which specification and disclosure ishereby incorporated herein by reference in its entirety and co-pendingprovisional patent application Ser. No. 61/537,461 filed Sep. 21, 2011,which specification pages 61-65, Example 26 (pg 106) and Examples 31-40(pgs 113-124) disclosure are hereby incorporated herein by reference. Itshould be appreciated that the general methods above and specificexamples below are illustrative only, for the purpose of assistance andof understanding the present invention, and should not be construed aslimiting the scope of the present invention in any manner.

Chromatography:

Unless otherwise indicated, crude product-containing residues werepurified by passing the crude material or concentrate through either aBiotage or Isco brand silica gel column (pre-packed or individuallypacked with SiO₂) and eluting the product off the column with a solventgradient as indicated. For example a description of (330 g SiO₂, 0-40%EtOAc/Hexane) means the product was obtained by elution from the columnpacked with 330 gms of silica, with a solvent gradient of 0% to 40%EtOAc in Hexanes.

Preparative HPLC Method:

Unless otherwise indicated, the compounds described herein were purifiedvia reverse phase HPLC using one of the following instruments: Shimadzu,Varian, Gilson; utilizing one of the following two HPLC columns: (a) aPhenomenex Luna or (b) a Gemini column (5 micron or 10 micron, C18,150×50 mm)

A typical run through the instrument included: eluting at 45 ml/min witha linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water(0.1% TFA) over 10 minutes; conditions can be varied to achieve optimalseparations.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Brukerseries 300 MHz instrument or a Bruker series 400 MHz instrument. Whereso characterized, all observed protons are reported as parts-per-million(ppm) downfield from tetramethylsilane (TMS) or other internal referencein the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method (commonlyreferred to as an ESI MS) utilizing a PE SCIEX API 150EX MS instrumentinstrument or an Agilent 1100 series LC/MSD system. Compounds having anisotopic atom, such as bromine and the like, are generally reportedaccording to the detected isotopic pattern, as appreciated by thoseskilled in the art.

The compounds disclosed and described herein have been named usingeither (1) the naming convention provided with Chem-Draw Ultra 11.0software, available in Chem Office, or (2) by the ISIS database software(Advanced Chemistry Design Labs or ACD software).

Example 1-A

Synthesis of 2-Bromo-7-methoxy-9H-xanthen-9-one

Step 1: 2-(4-Bromophenoxy)-5-methoxybenzoic acid

A RBF equipped with a reflux condenser was charged with2-bromo-5-methoxy benzoic acid (430 g, 1.8614 mol), 4-bromo phenol (322g, 1.8614 mol, 1 eq), potassium carbonate (514.5 g, 3.7 228 mol, 2.0 eq)and CuOTf-toluene complex (24.08 g, 0.04653 mol, 0.025 eq). Ethylacetate (9.0 ml 0.09679 mol, 0.052) and toluene (1.3 L) was carefullyadded portion wise. After stirring at RT for 10 min, the mixture washeated to 50° C. and stirred for 30 min. The mixture was then heated to110° C. for 20 hrs. The reaction was monitored by TLC. After 20 hrs, TLCshowed total consumption of starting materials. The reaction mixture wascooled to RT, diluted with water and acidified by 2N HCl. The reactionmixture was extracted with ethyl acetate (3.0×2 liter) followed byfilteration of the extract through celite bed and washing with ethylacetate (1.0 liter). Combined extracts were dried over sodium sulfateand concentrated to yield a crude mass of 590 g. (Dark brown solid).This mass was used directly in step 2.

Step 2: 2-Bromo-7-methoxy-9H-xanthen-9-one

To 2-(4-bromophenoxy)-5-methoxybenzoic acid (530 g, 1.6401 mol) wasadded sulfuric acid (1.6 lit, 3 vol.) at RT. The resulting dark mixturewas heated to 60 C. TLC showed complete conversion of starting materialto product after about 1 hr. The brown solution was cooled to RT andpoured onto ice with manual stirring. The resulting tan precipitate wascollected by filtration, washed with water, 1N NaOH (2.0 lit) solutionand finally with 800 mL of ethanol & stirred in 2 liters of acetone &filtered. The solids were dried under vacuum to afford 1.3 kg (68.85%)of the titled compounds as a white solid. MS m/z=307.0 [M+H]⁺. Calc'dfor C₁₄H₉BrO₃: 305.1.

Example 1-B

Synthesis of 7-Bromo-3-fluoro-2-methoxy-9H-xanthen-9-one

The titled compound was prepared using 2-bromo-4-fluoro-5-methoxybenzoicacid as the starting material, which starting material was prepared asfollows:

Step 1: 4-Bromo-2-fluoro-5-methylphenol

2-fluoro-5-methylphenol (23.8 g, 0.19 mol) and bromine (9.7 ml, 0.19mol) are combined in 50 ml of glacial acetic acid and stirred at RT forone hour. Acetic acid was removed under vacuum. The liquid was dilutedwith ethyl acetate and washed with water. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated to afford 4-bromo-2-fluoro-5-methylphenol (38 g, 98% yield)as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.98 (s, 1 H) 2.22 (s, 3 H) 6.81 (dd, J=9.15, 0.54Hz, 1 H) 7.17 (d, J=9.88 Hz, 1 H)

Step 2: 1-Bromo-5-fluoro-4-methoxy-2-methylbenzene

4-Bromo-2-fluoro-5-methylphenol (40 g, 0.19 mol), cesium carbonate (75g, 0.23 mol), and iodomethane (15 ml, 0.23 mol) were combined in 100 mlof DMF and stirred at RT for one hour (exothermic). The solution wasdiluted with ethyl acetate and filtered. The solution was washed withwater twice, dried with anhydrous sodium sulfate, filtered, andconcentrated. The product was purified via silica gel columnchromatography (RediSep 330 g column) using 0-50% ethyl acetate inhexane to afford 1-bromo-5-fluoro-4-methoxy-2-methylbenzene (38 g, 89%yield) as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 2.24 (s, 3 H) 3.76 (s, 3 H) 6.73 (d, J=8.80 Hz, 1 H)7.13 (d, J=10.56 Hz, 1 H)

Step 3: 2-Bromo-4-fluoro-5-methoxybenzoic acid

Potassium permanganate (53 g, 3.4 mol) was added to a solution of1-bromo-5-fluoro-4-methoxy-2-methylbenzene (37 g, 1.7 mol) in 75 ml ofpyridine and 150 ml of water at 60° C. The solution was stirred at 60°C. degrees for 24 hours. The solution was filtered and the solids werewashed with a solution of water/methanol (50:50). The filtrate wasconcentrated to approximately 100 ml, then acidified (pH 1) withconcentrated HCl. The solid was collected by filtration and dried undervacuum to afford 2-bromo-4-fluoro-5-methoxybenzoic acid as an off whitesolid. MS m/z=248.9 [M+H].

Step 4: 7-Bromo-2-fluoro-3-methoxy-9H-xanthen-9-one

Sulfuric acid (41 ml, 765 mmol) was added to2-bromo-4-fluoro-5-methoxybenzoic acid (3.75 g, 12 mmol) at RT. Thereaction mixture was stirred at 60° C. for 60 min. LCMS showed completereaction. The reaction mixture was cooled to RT and poured slowly overstirred mixture of ice and water (100 ml). The tan precipitate wasfiltered and washed with water (3×30 ml), twice with 30 ml of 0.5N NaOH,and with water again. The residue was recrystallized from 40 ml THF togive the title compound. MS m/z=326.2 [M+H]⁺. Calc'd for C₁₄H₉BrO₃:325.1.

Example 2

Synthesis of 8-Bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one

-   Step 1: A RBF was charged with 3-chloro-2-cyanopyridine (40 g, 289    mmol), 4-bromophenol (49.9 g, 289 mmol) and cesium carbonate (113 g,    346 mmol). The reactants were suspended in 50 mL of DMSO and allowed    to stir at 85 C overnight. The reaction was cooled to RT and 600 mL    of water was added to it. The reaction was filtered and the solid    washed with water, then air dried to provide    3-(4-bromophenoxy)-picolinonitrile as a tan solid.-   Step 2: A mixture of 3-(4-bromophenoxy)-picolinonitrile (57 g, 207    mmol) and 300 g of PPA was stirred at 190° C. for 2 h, followed by    180° C. overnight. After cooling to RT, the reaction mixture was    poured into 500 g of ice water. After the PH was adjusted to 7 with    KOH, the suspension was filtered. The solid was washed with large    excess of water, followed by washing with methanol and acetone. The    resulting solid was air dried to give    8-bromo-10H-chromeno[3,2-b]pyridin-10-one as a tan solid with >90%    purity. The material was carried on to the next step.-   Step 3: To a solution of 8-bromo-10H-chromeno[3,2-b]pyridin-10-one    (60 g, 217 mmol) and urea peroxide (42.9 g, 456 mmol) in 120 mL of    DCM at 0° C. was added dropwise trifluoroacetic anhydride (63.9 mL,    456 mmol). The resulting reaction was stirred for 2 h. The reaction    was quenched with 10% Na₂S₂O₃, extracted with DCM, dried over Na₂SO₄    and evaporated to dryness to give crude    8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide as a pale yellow    solid.-   Step 4: To a suspension of    8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide in 100 mL of    toluene at 0° C. was added dropwise phosphorus oxychloride (35.8 mL,    391 mmol) followed by 2 mL of DMF and the mixture was stirred at RT    overnight. The solvent was evaporated under vacuum and the residue    which crashed out of water, was filtered and washed with water,    methanol and acetone in sequence. The solid was air dried to give    8-bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one as a tan solid.

Example 3

Synthesis of 7-Bromo-3-methoxy-5H-chromeno[2,3-b]pyridin-5-one

-   Step 1: A three neck 3-L RBF equipped with an overhead stirred was    charged with 6-fluoropyridin-3-ylboronic acid (105 g, 745 mmol) and    1 L of THF. The mixture was cooled to 0° C. and NaOH 6N (373 mL,    2235 mmol) was added. To the resulting mixture was added hydrogen    peroxide 30% (126 mL, 4098 mmol), dropwise via an addition funnel    over the course of 30 minutes. After stirring at 0° C. for 2 hours    the mixture was removed from the ice bath and maintained at RT for    30 minutes. The reaction was acidified to pH 7 with 6 N HCl (ca. 300    mL) and diluted with 500 mL of ether. The aqueous layer was    extracted with ether (2×1 L) and the combined organic layers were    washed with water (1.5 L) then brine before being dried over sodium    sulfate. Filtration and concentration provided a white solid that    was dried on high vac overnight to provide 6-fluoropyridin-3-ol.-   Step 2: To a solution of 6-fluoropyridin-3-ol (75 g, 663 mmol) in    DMF (265 mL, 663 mmol) were added potassium carbonate (59.7 g, 995    mmol) and iodomethane (108 g, 763 mmol). The resulting slurry was    heated at 100° C. for 3 hours. The reaction was diluted with water    (1000 mL) and poured into a separatory funnel containing diethyl    ether (1000 mL). The layers were separated and the aqueous layer was    extracted with diethyl ether (4×500 mL). The combined organic layers    were washed with water and then brine, dried over sodium sulfate,    filtered and concentrated in vacuo to provide a yellow oil. This oil    was diluted with 500 mL of DCM and concentrated to provide a yellow    oil with a large amount of an off white precipitate. The mixture was    filtered and the derived solid was washed well with DCM. The    filtrate was concentrate to provide a mixture consisting of a yellow    oil and an off white solid. The solid was filtered, washing with    DCM. Repeat this procedure again and then concentrated the filtrate    to provide a yellow oil. The oil was taken up in 100 mL of ether and    flashed through a plug of silica gel with 10:1 hexanes:ether to    provide 2-fluoro-5-methoxypyridine as a yellow oil.-   Step 3: To a solution of DIPA (54.0 mL, 385 mmol) in THF (1101 mL,    385 mmol) at −60° C. was added BuLi, 2.5 M in hexanes (154 mL, 385    mmol) over 5 minutes such that the internal temperature was    maintained below −60° C. After stirring for 45 minutes at −65° C. a    solution of 2-fluoro-5-methoxypyridine (49 g, 385 mmol) in 200 mL of    THF was added over the course of 2 minutes maintaining an internal    temperature <−65° C. The reaction was stirred at −70° C. for 1.5    hours then reaction was poured into a 3 L flask containing 1200 g of    crushed dry ice. The reaction was allowed to warm to 0° C. and then    poured into 1000 mL of water. The organics were removed under    reduced pressure and the aqueous layer was acidified with 1100 mL of    2 N HCl. The resulting thick white slurry was stirred for 1 hour    then filtered to provide 2-fluoro-5-methoxynicotinic acid as a white    solid.-   Step 4: To a slurry of sodium hydride (60% dispersion) (21.74 g, 543    mmol) in DMF (351 mL, 175 mmol) at 0° C. was added 4-bromophenol    (60.7 g, 351 mmol) over the course of 5 minutes. Stirred at 0° C.    for two minutes then removed from the ice bath and stirred for an    additional 5 minutes at room temperature. Added    2-fluoro-5-methoxynicotinic acid (30 g, 175 mmol) portionwise over    10 minutes and heated the resulting slurry at 140° C. After cooling    to RT the mixture was then poured onto 1 kg of ice and was quenched    with acetic acid (50.2 mL, 877 mmol) and then 75 mL of 6 N HCl.    Stirred vigorously for 1 hour, leading to the formation of a red    slurry containing a very fine white precipitate. The slurry was    filtered to provide 2-(4-bromophenoxy)-5-methoxynicotinic acid.-   Step 5: A 2 L RBF charged with polyphosphoric acid (115% H₃PO₄) (300    g, 89 mmol) was heated to 140° C. at which point    2-(4-bromophenoxy)-5-methoxynicotinic acid (29 g, 89 mmol) was    introduced. The thick viscous mixture is slowly stirred while    heating at 140° C. After heating for 2.5 hours the solution was    cooled to 100° C. and then poured onto 1 kg of ice, leading to the    formation of a yellow taffy mixture. The slurry was vigorously    stirred for 1 hour leading to the formation of a fine white    precipitate. Filtration of this mixture proceeded slowly to provide    an off white solid. This solid was washed well with DCM. The    filtrate, which contained the desired product, was washed with brine    and concentrated to provide    7-bromo-3-methoxy-5H-chromeno[2,3-b]pyridin-5-one as an off-white    solid.

Example 4

Synthesis of 7-Bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one

-   Step 1: A 500 mL RBF was charged with 2-fluoro-3-hydroxypyridine    (3487 mg, 30.8 mmol), 2,5-dibromobenzoic acid (8630 mg, 30.8 mmol),    copper (I) trifluoromethane-sulfonate toluene complex (2:1) (399 mg,    0.771 mmol) and cesium carbonate (2.01E+04 mg, 61.7 mmol). To this    was added 100 mL of toluene and the mixture was azeotroped to remove    about 20 mL of toluene under reduced pressure. Reaction mixture was    then flushed with N2 and was heated to 120° C. for 2 hours. LC-MS    analysis showed formation of the desired product along with    significant impurities. The reaction mixture was cooled to RT and    concentrated to give a gummy residue. The residue was taken up in    ethyl acetate (100 mL) and water (75 mL). The aqueous layer was    neutralized with 1N HCl to pH˜2.0-3.0. The aqueous layer was    extracted with ethyl acetate (2×150 mL), separated, dried over    anhydrous sodium sulfate, and concentrated to yield the crude    product as a brown solid which was used directly in the next step.-   Step 2: A mixture of crude    5-bromo-2-(2-fluoropyridin-3-yloxy)benzoic acid (8.00 g, 25.6 mmol),    diethylamine (6.63 mL, 64.1 mmol) and TBTU (8.23 g, 25.6 mmol) in 8    mL of DMF was stirred overnight. The reaction was quenched with Sat.    NaHCO3, extracted with EA/H=2:1, washed with brine, dried over Na2    SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA 100:5 to    100:10 to 100:20 to 3:1) gave    5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide as a yellow    solid.-   Step 3: To a solution of    5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide (1.4 g,    3.81 mmol) and urea peroxide (1.076 g, 11.44 mmol) in 10 mL of DCM    at 0 C was added dropwise trifluoroacetic anhydride (1.601 mL, 11.44    mmol) and the resulting reaction was stirred overnight. LCMS showed    only less than 50% of desired conversion. The mixture was evaporated    to dryness, quenched with Sat. NaHCO₃, extracted with EA, dried over    Na₂SO₄, filtered and evaporated to dryness. CC (DCM to DCM/EA=3:1 to    DCM/MeOH=100:2 to 100:5 to 100:10) gave    3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide as    an offwhite solid.-   Step 4: To a solution of    3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide    (420 mg, 1.096 mmol) in 15 mL of DCM was added dropwise phosphorus    oxychloride (301 μL, 3.29 mmol) followed by 2 drops of DMF. After    stirring at rt for 1 h, the reaction was quenched with sat. NaHCO₃,    extracted into EtOAc, dried over Na₂SO₄, filtered and concentrated    under reduced pressure. The crude was purified by column    chromatography (DCM to DCM/EtOAc gradient beginning from 10:1 to 5:1    to 3:1) gave    5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide as    a colorless gum.-   Step 5: To a solution of    5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide    (120 mg, 0.299 mmol) in 5 mL of dry THF at 78° C. was added dropwise    lithium diisopropylamide, 2.0 m heptane/tetrahydrofuran/ethylbenzene    (158 μL, 1.195 mmol) (0.6 mL of 2M solution) and the reaction was    stirred at −78° C. for 3 h. The reaction was quenched at −78° C.    with sat. NH₄Cl and was allowed to warm up to RT. The reaction was    extracted with ETOAc, dried over Na₂SO₄, filtered and evaporated to    dryness. The crude was purified by column chromatography (1:1    hexane/DCM to 100% DCM) to give the titled compound,    7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one, as an    offwhite solid. MS (M+1): 328.

Example 5

Synthesis of 2-(2-bromo-5-methoxyphenyl)acetic acid

To a solution of 2-(3-methoxyphenyl)acetic acid (4.50 g, 27.1 mmol) inDCM (25 ml), was added bromine (1.40 ml, 27.1 mmol) dropwise at 0° C.(ice-water bath). The mixture was stirred overnight at RT and quenchedby addition of 5% sodium thiosulfate solution. The organic layer waswashed with brine, dried with MgSO₄ and concentrated under a stream ofnitrogen to give the titled compound, 2-(2-bromo-5-methoxyphenyl)aceticacid as white crystalline solid.

Example 6 (Intermediate B)

Synthesis of2-amino-2′-bromo-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one

-   Steps 1 and 2: A 100 ml RBF was charged with 4-bromophenol (6.7 g,    39 mmol), 2-(2-bromo-5-methoxyphenyl)acetic acid (Example 5, 6.3 g,    26 mmol) and copper (I) trifluoromethanesulfonate 2:1 toluene    complex (0.33 g, 0.64 mmol). Toluene (25 ml) and EtOAc (0.13 ml, 1.3    mmol) were added followed by cesium carbonate (17 g, 51 mmol) and    the mixture was stirred for 24 hrs under argon gas at 110° C. After    cooling to RT the mixture was filtered through Celite and the    resulting solids were washed with EtOAc. The filtrate was acidified    with 2N HCl and the layers were separated. The organic layer was    washed with brine, dried and concentrated to give the diaryl ether    as a crude material. The crude residue was treated with    polyphosphoric acid (45 g) and heated at 90° C. for 4 hrs until the    starting material was consumed. The resulting viscous mixture was    carefully transferred to an ice-water mixture (˜250 ml) and the    resulting suspension was extracted with EtOAc. The organic layer was    washed with brine, dried and concentrated to give a brown oil which    was purified by flash chromatography on silica gel, using 0-30%    ethyl acetate in hexane as the elution solvent gradient, to afford    2-bromo-8-methoxydibenzo[b,f]oxepine-10,11-dione.-   Step 3: To a solution of    2-bromo-8-methoxydibenzo[b,f]oxepin-10(11H)-dione (2.8 g, 8.77 mmol)    in dioxane (45 mL) and water (5 mL) was added selenium dioxide    (1.947 g, 17.55 mmol) and the mixture was stirred at 85° C. for 3    hrs. An extra 0.5 equiv. of selenium dioxide (0.45 g) was added and    the mixture was stirred for an additional hour, then concentrated in    vacuo and diluted with EtOAc. The organic layer was separated,    washed with water, saturated NaHCO₃, brine again, and concentrated    on silica (−20 mL). The product was purified using flash    chromatography on silica gel eluting with a solvent gradient of    0-60% EtOAc in hexane, to afford    2-bromo-8-methoxydibenzo[b,f]oxepine-10,11-dione as a yellow solid.-   Step 4: A 250 ml RBF was charged with    2-bromo-8-methoxydibenzo[b,f]oxepine-10,11-dione (1.17 g, 3.51 mmol)    in dioxane (30 mL) and EtOH (20 mL). 1-Methylguanidine HCl (1.539 g,    14.05 mmol) and sodium carbonate (2M solution) (10.54 mL, 21.07    mmol) were added and the mixture was stirred at 85° C. for 2 hrs.    The mixture was diluted with water to dissolve precipitated solids    and the mixture was concentrated in vacuo to about ¼ the volume. The    resulting brown precipitate was filtered, washed with water and    dried under air for 3 hrs. The resulting solid was triturated with    20 ml of DCM and filtered. The filtrate was concentrated and    purified by flash chromatography on silica gel using 10-80%    DCM/MeOH/NH4OH (90:10:1) in DCM to afford    2-amino-2′-bromo-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one    as a tan solid.

Example 7 (Intermediate C)

Synthesis of2-amino-2′-bromo-4′-fluoro-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one

-   Step 1: A 500 ml RBF was charged with    2-(2-bromo-5-methoxyphenyl)acetic acid (19.9 g, 81 mmol), toluene    (162 mL), 4-bromo-2-fluorophenol (13.34 mL, 122 mmol), copper(I)    triflate toluene complex (1.050 g, 2.030 mmol). Cesium carbonate    (52.9 g, 162 mmol) was added in portions at RT. After CO₂ evolution    ceased, the flask was equipped with reflux condenser and heated at    110° C. overnight. The mixture was cooled to RT and diluted with 200    ml of water. The organic layer was separated and discarded. The    aqueous layer was again washed with ETOAc and the organic layer was    discarded. The aqueous layer was acidified to pH 1 with 1N HCl and    stirred for 30 min at RT. The resulting oil crystallized to a    precipitate, which was filtered off, washed with water twice and    dried on air for 3 hrs. The solid was redissolved in 100 ml of hot    i-PrOH and water (˜150 ml) was added. The mixture was allowed to    crystallize for 2 hr at room temperature. The solid was filtered off    and dried on air to afford    2-(2-(4-bromo-2-fluorophenoxy)-5-methoxyphenyl)acetic acid.-   Step 2: 2-(5-Bromo-3-fluoro-2-(4-methoxyphenoxy)phenyl)acetic acid    (5 g, 14.08 mmol) was added to polyphosphoric acid (75 g, 14.08    mmol) preheated to 85° C. in 100 ml flask and mixed well with    spatula. The viscous mixture was heated at 85° C. for 5 hrs. The    mixture was cooled to RT and ˜50 g of ice was added directly to the    flask. The mixture was stirred with spatula and more ice was added.    After extraction with 100 ml EtOAc organic layer was washed with    water, 1N NaOH, brine and concentrated. The dark resulting residue    was dissolved in ˜5 ml of DCM and loaded onto 20 g silica gel    pre-column. The product was purified by flash chromatography on 80 g    RediSep column using 0-20% hexane/ethyl acetate gradient to afford    2-bromo-4-fluoro-8-methoxydibenzo[b,f]oxepin-10(11H)-one as white    solid.-   Step 3: To a solution of    8-bromo-4-fluoro-2-methoxydibenzo[b,f]oxepin-10(11H)-one (1.75 g,    5.19 mmol) in DMSO (26.0 mL), was added HBr (48%) (5.87 mL, 51.9    mmol) and the mixture was stirred at 65° C. for 4 hrs and then left    overnight at room temperature. The mixture was diluted with water    (100 ml) and extracted with EtOAc (50 ml). The organic layer was    washed twice with water and concentrated to afford    8-bromo-4-fluoro-2-methoxydibenzo[b,f]oxepine-10,11-dione.-   Step 4: 2-Bromo-4-fluoro-8-methoxydibenzo[b,f]oxepine-10,11-dione    (1.8 g, 5.13 mmol) was dissolved, by heating to ˜70° C., in the    mixture of dioxane (29.3 mL) and EtOH (43.9 mL), then cooled to RT    and 1-methylguanidine HCl (2.247 g, 20.51 mmol) was added followed    by sodium carbonate (2M solution) (15.38 mL, 30.8 mmol). The color    of the mixture immediately changed from bright yellow to light    brown. The mixture was then stirred at 85° C. for 1. The mixture was    cooled, diluted with ˜25 ml of EtOAc and decanted from the solid.    The solid was dissolved by addition of ˜15 ml of water and was    combined with organic extract. Organic layer was washed twice with    brine and concentrated to leave a brownish solid. The solid was    treated with 30 ml of DCM and sonicated for 5 min. White solid was    filtered and washed with DCM. The solids which precipitate from the    filtrate were filtered, washed with DCM and dried on air to afford    pure product. The filtrate was concentrated in vacuo and the 5 ml    DCM was added to the crude residue resulting in an additional second    crop of solid desired product (major isomer)    2-amino-2′-bromo-4′-fluoro-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one.

Example 8 (Method A1)

Synthesis of2-amino-2′-methoxy-1-methyl-7′-(pyrimidin-5-yl)spiro[imidazole-4,9′-xanthen]-5(1H)-one

A 15 ml resealable vial was charged with2-amino-2′-bromo-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one(87 mg, 224 μmol), pyrimidin-5-ylboronic acid (56 mg, 448 μmol) andtetrakis(triphenylphosphine)palladium(0) (26 mg, 22 μmol). DME (1 ml)was added to the mixture, and the vial was capped with argon. Sodiumcarbonate (2M aq. solution) (336 μl, 672 μmol) was added and the vialwas sealed and heated at 85° C. for 16 hr. The heterogeneous mixture wascooled to RT, diluted with 5 ml EtOAc and 2 ml water, then filtered andthe solids were washed with water (5 ml). The solids were redissolved inDCM/MeOH and dried with MgSO4, filtered and concentrated in vacuo toafford2-amino-2′-methoxy-1-methyl-7′-(pyrimidin-5-yl)spiro[imidazole-4,9′-xanthen]-5(1H)-oneas brownish solid.

Example 9 (Method A2)

Synthesis of2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoropyridin-3-yl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one-TFAsalt

-   Step 1: To a solution of    2-amino-2′-bromo-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one    (200 mg, 0.515 mmol) in DCM (2576 μL) boron tribromide (1M in DCM)    (1082 μL, 1.082 mmol) was added at RT. The mixture was stirred for    1.5 hr and neutralized by addition of aq. NaHCO₃. DCM was removed in    the stream of nitrogen and the residue was filtered, washed with    water and dried to afford    2-amino-2′-bromo-7′-hydroxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one.-   Step 2: A 15 mL resealable tube was charged with    2-amino-2′-bromo-7′-hydroxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one    (365 mg, 0.975 mmol), tetrakis(triphenylphosphine) palladium (0)    (113 mg, 0.098 mmol), 2-fluoropyridin-3-ylboronic acid (234 mg,    1.658 mmol) DMF (4877 μL) and sodium carbonate (2M solution) (1463    μL, 2.93 mmol). The mixture was stirred under argon for 3 hrs at    85° C. The mixture was diluted with EtOAc and water. The organic    layer was separated and washed with water and brine, dried over    magnesium sulfate and concentrated. The residue was purified by    flash chromatography on silica gel to afford    2-amino-2′-(2-fluoropyridin-3-yl)-7′-hydroxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one.-   Step 3: To a suspension of    2-amino-2′-(2-fluoropyridin-3-yl)-7′-hydroxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one    (131 mg, 0.348 mmol) in DCM (3 mL) triethylamine (97 μL, 0.697 mmol)    and    1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide    (187 mg, 0.523 mmol) were added and the mixture was stirred for 4    hrs. Additional TEA (100 mkL) and N-phenyl triflimide (150 mg) were    added and the mixture was stirred for an additional 2 hrs until    consumption of the starting material. The reaction mixture was    diluted with DCM and quenched with NaHCO₃ (5 ml). The organic layer    was filtered through celite and concentrated to afford    2-amino-2′-(2-fluoropyridin-3-yl)-1-methyl-5-oxo-1,5-dihydrospiro[imidazole-4,9′-xanthene]-7′-yl    trifluoromethanesulfonate, which was used without further    purification.-   Step 4: A 15 mL resealable tube was charged with    2-amino-2′-(2-fluoropyridin-3-yl)-1-methyl-5-oxo-1,5-dihydrospiro[imidazole-4,9′-xanthene]-7′-yl    trifluoromethanesulfonate (178 mg, 0.34 mmol),    2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane    (114 mg, 0.544 mmol), tetrakis(triphenylphosphin)-palladium (0)    (39.3 mg, 0.034 mmol), DMF (1700 μL) and sodium carbonate (2M    solution) (510 μL, 1.020 mmol). The vial was sealed and the reaction    was stirred for 2 hrs at 85° C. The mixture was partitioned between    water (3 mL) and EtOAc (5 ml). The organic layer was loaded onto 2 g    SCX column and washed with EtOAc, DCM and MeOH. The material was    recovered from the column with 2 M ammonia in MeOH, concentrated and    purified by reverse phase HPLC (Gilson, 15-90% MeCN in 0.1% aq.    TFA). The pure fractions were combined, concentrated and lyophilized    overnight to give    2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoropyridin-3-yl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one    as the 2,2,2-trifluoroacetate (TFA) salt.

Example 10 (Intermediates 1, 1-A and 1-B)

Synthesis of tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′(3′H)-ylidenecarbamate

-   Step 1: A mixture of    7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (740 mg,    2.25 mmol; Example 4), 2-methyl-2-propane-sulfinamide (819 mg, 6.76    mmol), and tetraethoxytitanium (6.07 mL, 29.3 mmol) in dry THF (15    mL) was heated at 75° C. for 24 hours under nitrogen atmosphere. The    mixture was cooled to RT and brine and aqueous saturated bicarbonate    solution were added while the mixture was rapidly stirred. After 1    h, the resulting suspension was filtered through celite, and the    filter cake was washed with EtOAc. The filtrate was washed with    brine and dried over MgSO₄. The solvent was removed under reduced    pressure and the remaining residue was purified by flash    chromatography on silica gel (0-20% EtOAc/hexanes) to afford 3.3 g    of    N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide    as an orange solid.-   Step 2: To a solution of methyl acetate (745 μL, 9.38 mmol) in THF    (25 mL) was added dropwise LDA (2.0M in heptane/THF/ethylbenzene;    5038 μL, 10.08 mmol) at −78° C. under nitrogen atmosphere. The    reaction mixture was allowed to stir for 30 min at −78° C. and a    solution of chlorotitanium triisopropoxide (2402 μL, 10.08 mmol) in    THF (15 mL) was added dropwise. After 30 min a solution of    N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide    (1500 mg, 3.47 mmol) in THF (30 mL) was added dropwise. After 5 min    saturated aqueous NH₄Cl solution was added and the suspension was    warmed to RT. Water was added and the organic phase was separated.    The organic phase was dried over MgSO₄ and the solvent was removed    under reduced pressure. The residue was purified by flash    chromatography on silica gel (20-70% EtOAc/hexanes) to obtain 1.60 g    of methyl    2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate    as a yellow powder.-   Step 3: To a solution of methyl    2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate    (510 mg, 1.008 mmol) in MeOH (15 mL) was added HCl (4.0M in    1,4-dioxane; 5.04 mL, 20.17 mmol). After 30 min the solvents were    removed under reduced pressure. The residue was dissolved in MeOH (4    mL) and the solvent was evaporated to yield quantitatively methyl    2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate    as a yellow solid which was used in the next step without further    purification.-   Step 4: To a solution of methyl    2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate    HCl (200 mg, 0.457 mmol) in DMF (2 mL) was added EDCI.HCl (175 mg,    0.913 mmol), N-(tert-butoxycarbonyl)-N′-methylthiourea (347 mg,    1.826 mmol, prepared according to Synth. Commun. 2008, 38, 3834) and    DIPEA (0.794 mL, 4.57 mmol). The reaction mixture was allowed to    stir at RT overnight. The reaction mixture was diluted with EtOAc    and washed with brine. The organic phase was separated and dried    over MgSO₄. The solvent was removed under reduced pressure. The    remaining residue was purified by flash chromatography on silica gel    (20-100% EtOAc/hexanes) to obtain 166 mg methyl    2-(7-bromo-5-(2-(tert-butoxycarbonyl)-3-methylguanidino)-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate    as a yellow oil.-   Step 5: DIPEA (1703 μL, 9.79 mmol) was added to a solution of methyl    2-(7-bromo-5-(2-(tert-butoxycarbonyl)-3-methylguanidino)-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate    (546 mg, 0.979 mmol) in EtOH (10 mL). The reaction was allowed to    stir at RT for 20 minutes. The reaction mixture was concentrated    under reduced pressure to afford 510 mg of tert-butyl    7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate    as a yellow solid which was used in the next step without further    purification.-   Step 6: Chiral separation of racemic tert-butyl    7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate

(Intermediate 1)

Tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamatewas chromatographed using supercritical CO₂ (additives 20% MeOH with0.2% DEA) on a Chiralpak IC column (21×250 mm, 5 μm) eluting at a flowrate 80 ml/min (100 bar pressure, 40° C. column temperature). The firstpeak (retention time=5.47 min) provided (R)-tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(intermediate 1-A; >99% ee), and the second peak (retention time=5.48min) provided (S)-tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(intermediate 1-B; >99% ee).

Example 11

Synthesis of2′-amino-7-bromo-3-chloro-1-fluoro-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one-2,2,2-trifluoroacetate

DIPEA (0.094 ml, 0.538 mmol) was added to a solution of methyl2-(7-bromo-5-(2-(tert-butoxycarbonyl)-3-methylguanidino)-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yBacetate(30 mg, 0.054 mmol) in EtOH (1 ml). The reaction was allowed to stir atRT for 5 min. The solvent was removed under reduced pressure and theresidue was dissolved in DCM (1 mL). TFA (1 mL) was added and thereaction mixture was heated to 70° C. for 5 min. The solvent was removedunder reduced pressure and the residue was purified by preparativereversed-phase preparative HPLC using a Phenomenex Gemini column, 10micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH₃CN/H₂O, gradient 10% to100% over 20 min to obtain 30 mg of2′-amino-7-bromo-3-chloro-1-fluoro-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-oneTFA salt as a white solid.

MS m/z=424.9 [M+H]⁺, 427.0 [M+2H]⁺¹. Calculated forC₁₆H₁₁BrClFN₄O₂.C₂HF₃O₂: 539.66.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.35 (s, 3 H) 3.37-3.44 (m, 2 H) 7.39(d, J=8.77 Hz, 1 H) 7.66-7.76 (m, 2 H) 7.90 (d, J=1.46 Hz, 1 H)8.77-9.09 (m, 2 H) 10.25 (s, 1 H).

Example 12

Synthesis of2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one2,2,2-trifluoroacetate

A sealable vial was charged with tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(Example 10; 100 mg, 0.190 mmol), 2-fluoropyridin-3-ylboronic acid (37.5mg, 0.266 mmol),bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)(13.47 mg, 0.019 mmol) and potassium phosphate (0.047 mL, 0.571 mmol).The vial was evacuated and backfilled/purged 2× with nitrogen gas.Dioxane (3 mL) and water (1 mL) were added and the reaction mixture waspurged for 1 min with nitrogen gas. The vial was heated to 100° C. for10 min. The reaction mixture was partitioned between water and EtOAc.The organic phase was separated and dried over MgSO₄. The solvent wasremoved under reduced pressure. The residue was dissolved in DCM (3 mL),and TFA (1 mL) was added. The reaction mixture was allowed to stir for15 min at RT. The volatiles were removed under reduced pressure and theresidue was purified by preparative reversed-phase preparative HPLCusing a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1%TFA in CH₃CN/H₂O, gradient 10% to 100% over 20 min to obtain 41.6 mg of2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one2,2,2-trifluoroacetate as a white solid.

MS m/z=442.0 [M+H]⁺. Calculated for C₂₁H₁₄ClF₂N₅O₂.C₂HF₃O₂: 555.84 (TFAsalt).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.37 (s, 3 H) 3.45-3.53 (m, 2 H)7.47-7.59 (m, 3 H) 7.75-7.83 (m, 3 H) 7.86 (s, 1 H) 8.14 (ddd, J=10.08,7.75, 1.90 Hz, 1 H) 8.28 (d, J=4.82 Hz, 1 H) 8.93 (br. s., 2 H) 10.39(br. s., 1 H). Hz, 1 H) 8.21 (d, J=4.53 Hz, 1 H).

Example 13

Synthesis of2′-amino-1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

Tert-butyl1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamatewas obtained as a side product in the synthesis of Example 12. To asolution of tert-butyl1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(32 mg, 0.053 mmol) in DCM (2.5 mL) was added TFA (500 μL, 6.49 mmol).The reaction was allowed to stir at RT overnight. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inMeOH and loaded onto a Varian Bond Elut SCX column. The column waswashed with MeOH and subsequently eluted with a 2 M solution of ammoniain MeOH to obtain 22.6 mg2′-amino-1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-oneas a white solid.

MS m/z=503.0 [M+H]⁺. Calculated for C₂₆H₁₇F₃N₆O₂: 502.45.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.96 (s, 2 H) 3.46 (s, 3 H)7.28-7.32 (m, 1 H) 7.32-7.39 (m, 1 H) 7.40-7.47 (m, 1 H) 7.58-7.64 (m, 1H) 7.75-7.80 (m, 1 H) 7.88-7.99 (m, 2 H) 8.17-8.25 (m, 2 H) 8.54-8.63(m, 1 H).

Example 14

Synthesis of(R)-2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The title compound was synthesized by procedures and steps analogous tothose described in Example 12 above, but using (R)-tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(Intermediate 1-A) and 2-fluoropyridin-3-ylboronic acid.

MS m/z=442.0 [M+H]⁺. Calculated for C₂₁H₁₄ClF₂N₅O₂: 441.82.

¹H NMR (300 MHz, chloroform-d) δ ppm 2.63-2.90 (m, 2 H) 3.40 (s, 3 H)7.28 (br. s., 2H) 7.35-7.44 (m, 2 H) 7.49-7.63 (m, 2 H) 7.87 (ddd,J=9.79, 7.60, 1.90 Hz, 1 H) 8.12-8.32 (m, 1 H).

Example 15

Synthesis of(S)-2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The title compound was synthesized by procedures and steps analogous tothose described in Example 12 above, but using (S)-tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(Example 1-B) and 2-fluoropyridin-3-ylboronic acid.

MS m/z=442.0 [M+H]⁺. Calculated for C₂₁H₁₄ClF₂N₅O₂: 441.82.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.69-2.88 (m, 2 H) 3.40 (s, 3 H)7.29-7.33 (m, 1 H) 7.36 (s, 1 H) 7.40 (d, J=8.48 Hz, 1 H) 7.52-7.59 (m,2 H) 7.87 (ddd, J=9.76, 7.56, 1.97

Example 16

Synthesis of2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

-   Step 1: A sealable vial was charged potassium phosphate (440 mg,    2.075 mmol), 2-fluoropyridin-3-ylboronic acid (117 mg, 0.830 mmol)    and    bis[di-tert-butyl(4-dimethylaminophenyl)-phosphine]dichloropalladium(II)    (24.48 mg, 0.035 mmol). The vial was evacuated and backfilled with    nitrogen gas. The procedure was repeated twice. A solution of    tert-butyl    7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate    (Example 10; 363.6 mg, 0.692 mmol) in dioxane (5928 μL) was added    followed by water (988 μL). The reaction was heated to 60° C. for 12    minutes. The reaction was cooled to RT and diluted with water and    EtOAc. The organic layer was separated, washed with brine and dried    over sodium sulfate. The solvent was removed under reduced pressure.    The remaining residue was purified by flash chromatography on silica    gel (10-70% EtOAc/hexanes) to yield 230 mg of tert-butyl    3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate    as a white solid-   Step 2: A sealable vial was charged with tert-butyl    3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate    (75 mg, 0.138 mmol), potassium phosphate (0.034 mL, 0.415 mmol), and    bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)    (4.90 mg, 6.92 μmol). The vial was evacuated and backfilled 2× with    nitrogen gas. Dioxane (1 mL) followed by    2-cyclohexenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57.6 mg,    0.277 mmol) and water (0.167 mL) were added, and the reaction    mixture was heated to 80° C. for 30 minutes. The reaction was cooled    to RT and diluted with water and EtOAc. The organic layer was    separated, washed with brine and dried over sodium sulfate. The    solvent was removed under reduced pressure. The remaining residue    was purified by flash chromatography on silica gel (0-60%    EtOAc/hexanes) to afford tert-butyl    3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate    as an off white solid.-   Step 3: The solid from step 2 was dissolved in DCM (3 mL) and TFA    (400 μL, 5.19 mmol) was added. The reaction was allowed to stir at    RT overnight, then concentrated under reduced pressure. The residue    was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column.    The column was washed with MeOH and the product was subsequently    eluted with a 2 M solution of ammonia in MeOH. The eluate was    concentrated under reduced pressure to afford a light brown solid,    which was diluted in DCM (1 mL) and treated with hexanes (10 mL). A    white precipitate formed which was filtered off to obtain    2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one.

MS m/z=490.0 [M+H]⁺. Calculated for C₂₆H₂₁F₂N₅O₃: 489.47.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.37 (d, J=3.80 Hz, 2 H) 2.68-2.89(m, 2 H) 3.39 (s, 3 H) 3.84 (t, J=5.48 Hz, 2 H) 4.57 (d, J=1.75 Hz, 2 H)7.26 (s, 1 H) 7.28-7.33 (m, 1 H) 7.38 (d, J=8.48 Hz, 1 H) 7.49-7.56 (m,1 H) 7.58 (d, J=1.90 Hz, 1 H) 7.87 (ddd, J=9.76, 7.64, 1.75 Hz, 1 H)8.20 (d, J=4.68 Hz, 1 H)

Example 17

Synthesis of(S)-2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The titled compound was synthesized by procedures and steps analogous tothose described in Example 16 above, but using (S)-tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(Intermediate 1-A in Example 10).

MS m/z=490.1 [M+H]⁺. Calculated for C₂₆H₂₁F₂N₅O₃: 489.47.

¹H NMR (300 MHz, MeOH) δ ppm 2.37 (d, J=4.38 Hz, 2 H) 3.39 (d, J=6.43Hz, 2 H) 3.49 (s, 3 H) 3.83 (t, J=5.55 Hz, 2H) 4.55 (d, J=2.19 Hz, 2 H)6.78-6.86 (m, 1 H) 7.41-7.54 (m, 3 H) 7.72-7.81 (m, 2 H) 8.09 (ddd,J=9.94, 7.75, 1.90 Hz, 1 H) 8.22 (dt, J=4.82, 1.46 Hz, 1 H)

Example 18

Synthesis of2′-amino-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The titled compound was synthesized by procedures and steps analogous tothose described in Example 16 above.

MS m/z=503.0 [M+H]⁺. Calculated for C₂₆H₁₇F₃N₆O₂: 502.45.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.72-2.94 (m, 2 H) 3.43 (s, 3 H)7.31 (ddd, J=7.27, 5.15, 1.75 Hz, 1 H) 7.42-7.48 (m, 1 H) 7.52 (s, 1 H)7.54-7.59 (m, 2 H) 7.77 (d, J=5.41 Hz, 1 H) 7.84-7.92 (m, 2 H) 8.22 (d,J=4.97 Hz, 1 H) 8.31 (d, J=5.26 Hz, 1 H).

Example 19

Synthesis of(S)-2′-amino-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The titled compound was synthesized by procedures and steps analogous tothose described in Example 16 above, but using (S)-tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(Intermediate 1-A of Example 10).

MS m/z=503.0 [M+H]⁺. Calculated for C₂₆H₁₇F₃N₆O₂: 502.45.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.72-2.96 (m, 2 H) 3.43 (s, 3 H)7.30 (br. s., 1 H) 7.44 (d, J=8.62 Hz, 1 H) 7.53 (d, J=11.98 Hz, 3 H)7.76 (br. s., 1 H) 7.81-7.96 (m, 2 H) 8.21 (br. s., 1 H) 8.30 (d, J=4.82Hz, 1 H)

Examples 20, 20-A and 20-B

Synthesis of racemic tert-butyl7-bromo-3-chloro-1′-methyl-6′-oxo-5′,6′-dihydro1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′(3′H)-ylidenecarbamate

The compound Example 20 was synthesized by procedures and stepsanalogous to those described for Example 10 above, but using7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one. MS m/z=508.9 [M+H]⁺.Calculated for C₂₁H₂₀BrClN₄O₄: 507.76

¹H NMR (400 MHz, DMSO-d₆) d ppm 3.24-3.29 (m, 2H), 3.36 (s, 3H), 7.28(s, 2 H), 7.30 (s, 2 H), 7.54 (s, 1 H), 7.61-7.63 (m, 1 H), 7.63-7.65(m, 1H) 7.66 (d, J=2.35 Hz, 1H), 8.46 (s, 1 H).

Synthesis of (S)- and(R)-7-bromo-3-chloro-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one(Examples 20-A and 20-B)

Compound Examples 20-A and 20-B were obtained from racemic tert-butyl7-bromo-3-chloro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′(3′H)-ylidenecarbamateutilizing chiral separation conditions as described herein above forExample 10 followed by deprotection as described in Example 16 step 3.Mass for both peaks m/z=406.8 [M+H]⁺, 408.8 [M+2H]⁺. Calculated forC₁₆H₁₂BrClN₄O₂: 407.65

Examples 21, 21-A and 21-B

Synthesis of (R)- and(S)-7-(2-Fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one(Examples 21-A and 21-B)

The titled compound racemate (Example 21) was synthesized by proceduresand steps analogous to those described in Example 16, but usingtert-butyl7-bromo-3-chloro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′(3′H)-ylidenecarbamate(Example 20). MS m/z=485.0 [M+H]⁺. Calculated for C₂₆H₁₈F₂N₆O₂: 484.46

¹H NMR (400 MHz, DMSO-d₆) d ppm 2.72 (d, J=18.58 Hz, 1 H), 2.88-3.12 (2,3 H), 3.42 (s, 3H), 6.51 (s, 2 H), 7.41-7.55 (m, 2 H), 7.67 (d, J=7.83Hz, 1 H), 7.73 (s, 2 H), 7.95 (d, J=4.89 Hz, 1 H), 8.08 (t, J=9.63 Hz, 1H), 8.24 (d, J=12.91 Hz, 2 H), 8.39 (d, J=5.09 Hz, 1 H), 8.74 (s, 1 H).

Racemic7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-onewas chromatographed using supercritical CO₂ (additives 30% methanol) onan AD-H column (20×150 mm) eluting at a flow rate 70 ml/min (100 barpressure). The first peak (retention time=2.51 min) provided(R)-7-(2-Fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one(Example 21-A; >99% ee), and the second peak (retention time=5.55 min)provided(S)-7-(2-Fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one(Example 21-B; >99% ee).

Mass for both peaks m/z=485.0 [M+H]⁺. Calculated for C₂₆H₁₈F₂N₆O₂:484.46

Example 22

(S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The title compound was synthesized by procedures and steps analogous tothose described in Example 16, but using (S)-tert-butyl7-bromo-3-chloro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′(3′H)-ylidenecarbamate(Example 20-A).

MS m/z=472.2 [M+H]⁺. Calculated for C₂₆H₂₂FN₅O₃: 471.48

¹H NMR (400 MHz, DMSO-d₆) d ppm 2.61-2.75 (m, 2 H), 3.23 (s, 3 H), 3.84(s, 2 H), 4.21-4.37 (m, 2 H), 6.49 (s, 2 H), 6.66 (s, 2 H) 7.41 (d,J=8.41 Hz, 1 H), 7.46-7.53 (m, 2 H), 7.59 (s, 2 H), 7.63 (d, J=8.31 Hz,1 H), 8.09 (t, J=8.22 Hz, 1 H), 8.25 (d, J=3.72 Hz, 1 H), 8.54 (s, 1 H).

Example 23

(R)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-2′-imino-1′-methyl-2′,3′-dihydro-PH-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The titled compound was synthesized by procedures and steps analogous tothose described in Example 16, but using (R)-tert-butyl7-bromo-3-chloro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′(3′H)-ylidenecarbamate(Example 20-B). MS m/z=472.2 [M+H]⁺. Calculated for C₂₆H₂₂FN₅O₃: 471.48

Example 24

(S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoropyridin-3-yl)-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The titled compound was synthesized by procedures and steps analogous tothose described in Example 16, but using (S)-tert-butyl7-bromo-3-chloro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′(3′H)-ylidenecarbamate(Example 20-A). MS m/z=472.2 [M+H]⁺. Calculated for C₂₆H₂₂FN₅O₃: 471.48

¹H NMR (400 MHz, DMSO-d₆) d ppm 2.57-2.79 (m, 4 H), 3.24 (s, 3 H),3.63-3.85 (m, 2 H), 4.44-4.63 (m, 2 H), 6.37-6.71 (m, 4 H), 7.32-7.59(m, 4 H), 7.63 (d, J=8.31 Hz, 1 H), 8.08 (t, J=8.56 Hz, 1 H), 8.25 (d,J=3.13 Hz, 1 H), 8.50 (s, 1H).

Example 25

(R)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoropyridin-3-yl)-2′-imino-1′-methyl-2′,3′-dihydro-PH-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The titled compound was synthesized by procedures and steps analogous tothose described in Example 16, but using (R)-tert-butyl7-bromo-3-chloro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′(3′H)-ylidenecarbamate(Example 20-B). MS m/z=472.2 [M+H]⁺. Calculated for C₂₆H₂₂FN₅O₃: 471.48

Example 26

(S)-2′-amino-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The titled compound was synthesized by procedures and steps analogous tothose described in Example 16 above, but using (S)-tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(Intermediate 1-A of Example 10).

MS m/z=518.0 [M+H]⁺. Calculated for C₂₈H₂₅F₂N₅O₃: 517.53.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 6 H) 2.45-2.53 (m, 2 H)2.70-2.90 (m, 2 H) 3.40 (s, 3 H) 3.94 (s, 2 H) 6.64 (s, 1 H) 7.31 (s, 2H) 7.41 (s, 1 H) 7.51-7.56 (m, 1 H) 7.57-7.60 (m, 1 H) 7.82-7.92 (m, 1H) 8.18-8.25 (m, 1 H)

Example 27

(S)-2′-amino-3-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one

The titled compound was synthesized by procedures and steps analogous tothose described in Example 16 above, but using (S)-tert-butyl7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate(Intermediate 1-A of Example 10).

MS m/z=518.0 [M+H]¹¹. Calculated for C₂₈H₂₅F₂N₅O₃: 517.53.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J=2.19 Hz, 6 H) 2.43 (br.s., 2 H) 2.76 (q, J=16.22 Hz, 2 H) 3.37 (s, 3 H) 4.37 (d, J=2.63 Hz, 2H) 6.65 (d, J=1.46 Hz, 1 H) 7.27-7.32 (m, 1 H) 7.34-7.40 (m, 2 H)7.47-7.54 (m, 1 H) 7.54-7.59 (m, 1 H) 7.85 (ddd, J=9.79, 7.60, 1.90 Hz,1 H) 8.19 (dt, J=4.68, 1.53 Hz, 1 H)

Example 28

Synthesis of(4′S)-2′-amino-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one2,2,2-trifluoroacetate

A flask was charged with a mixture of(S)-2′-amino-3-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one(36.2 mg, 0.070 mmol) and(S)-2′-amino-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one(10.1 mg, 0.020 mmol). Ethanol (6 mL) was added and the flask wassealed, evacuated and backfilled with nitrogen. Palladium on activatedcarbon (10% wt.; 7.44 mg, 0.070 mmol) was added and the flask wasevacuated and backfilled with hydrogen. The flask was fitted with aballoon filled with H₂ gas (1 atm) and the reaction mixture was stirredfor 3 days at RT. Additional palladium on activated carbon (10% wt.;7.44 mg, 0.070 mmol) was added to the reaction mixture and the flask wasfitted with a balloon filled with H₂ gas (1 atm). The reaction mixturewas allowed to stir for additional 2 days at RT. The reaction mixturewas filtered through a pad of celite. The solvent was removed underreduced pressure and the residue was purified by preparativereversed-phase preparative HPLC using a Phenomenex Gemini column, 10micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH₃CN/H₂O, gradient 10% to100% over 11 min to afford 18.5 mg(4′S)-2′-amino-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one2,2,2-trifluoroacetate 2,2,2-trifluoroacetate as a white solid.

MS m/z=520.0 [M+H] Calculated for C₂₈H₂₇F₂N₅O₃.C₂HF₃O₂: 633.57 (TFAsalt)

¹H NMR (300 MHz, CHLOROFORM-d) d ppm 1.28 (s, 3 H) 1.32 (s, 3 H)1.58-1.72 (m, 1 H) 1.81 (d, J=10.96 Hz, 2 H) 3.16 (br. s., 3 H)3.05-3.13 (m, 2 H) 3.45-3.63 (m, 4 H) 3.74-3.94 (m, 2 H) 7.14 (br. s., 1H) 7.31 (d, J=6.28 Hz, 1 H) 7.47 (d, J=8.62 Hz, 1 H) 7.57 (br. s., 1 H)7.65 (d, J=8.62 Hz, 1 H) 7.94 (t, J=8.55 Hz, 1 H) 8.20 (d, J=4.24 Hz, 1H)

Example 40

Synthesis ofN-(2-amino-2′-methoxy-1-methyl-5-oxo-1,5-dihydrospiro[imidazole-4,9′-xanthen]-7′-yl)-5-chloropicolinamide

A 10 ml resealable tube was charged with2-amino-2′-bromo-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one(234 mg, 0.603 mmol) (Intermediate B, example 6), (+)-sodium L-ascorbate(11.94 mg, 0.060 mmol), sodium azide (118 mg, 1.808 mmol) and copper(I)iodide (22.96 mg, 0.121 mmol). Ethanol (2.1 ml), water (0.9 ml) andtrans-N,N′-dimethyl-1,2-cyclohexanediamine (0.029 ml, 0.181 mmol) wereadded, and the vial was sealed and heated at 85° C. for 18 hrs. Thereaction mixture was diluted with EtOAc (5 ml) and washed 3 times withwater then with brine and concentrated. The residue was diluted with 3ml THF and 1 ml water and treated with trimethylphosphine (1.0M solutionin THF) (0.603 ml, 0.603 mmol), and stirred for 20 min at RT. LCMS116872-50-8 of the reaction mixture revealed complete conversion of theazide to the aniline (peak at 1.12 min, M+H=325). The mixture wasconcentrated in vacuo, diluted with water and extracted with EtOAc. Theorganic layer was washed with brine and concentrated. The residue wasredissolved in 3 ml EtOAc, 5-chloro-2-pyridinecarboxylic acid (95 mg,0.603 mmol) and triethylamine (0.252 ml, 1.808 mmol) were added and themixture was cooled in ice-water bath. 1-Propanephosphonic acid cyclicanhydride (T3P) (50 wt. % solution in ethyl acetate) (0.718 ml, 1.206mmol) was added dropwise. The bath was removed and the mixture wasstirred at RT for 30 min, then quenched by addition of sat. NaHCO₃. Theorganic layer was washed twice with water, brine and concentrated. Theresidue was purified by column chromatography on 25 g PuriFlash columnusing 10-100% DCM/MeOH/NH₄OH (90:10:1) in DCM to affordN-(2-amino-2′-methoxy-1-methyl-5-oxo-1,5-dihydrospiro[imidazole-4,9′-xanthen]-7′-yl)-5-chloropicolinamideas off white solid. Found M+H=464.

The following compounds in Table I are additional representativeexamples of compounds of Formulas I, II and III, and sub-formulasthereof, provided by the present invention. The methods used to prepareexemplary compounds 8-9 and 29-40 are included in Table 1, andcorrespond to those described in the Examples 5-9 herein above. Themethods used to prepare the exemplary compounds 11-28 shown in Table 1are as described in the Example No. (“Eg”) so indicated and hereinabove. Table I further provides the mass and biological data (average nMIC₅₀'s for the enzyme and cell assays, provided in a range) for eachcompound, where available.

TABLE I BACE Ex- 1 HEK am- Ob- FRET cell ple served Meth- assay assay NoCompound Structure Compound Name MW od (uM) (uM)  8

(4R)-2-amino-2′- methoxy-1-methyl-7′- (5-pyrimidinyl) spiro[imida-zole-4,9′-xanthen]- 5(1H)-one, 388 A1 0.0134 0.108

(4S)-2- amino-2′-methoxy-1- methyl-7′-(5- pyrimidinyl)spiro [imidazole-4,9′-xanthen]- 5(1H)-one  9

(4R)-2-amino-2′-(3,6- dihydro-2H-pyran-4- yl)-7′-(2-fluoro-3-pyridinyl)-1- methylspiro[imidazole- 4,9′-xanthen]-5(1H)- one and 457 A20.0009 0.0036

(4S)-2-amino-2′-(3,6- dihydro-2H-pyran- 4-yl)-7′-(2-fluoro-3-pyridinyl)-1- methylspiro[imidazole- 4,9′-xanthen]-5(1H)- one 29

(4R)-2-amino-4′- fluoro-7′-methoxy-1- methyl-2′-(4-methyl-phenyl)spiro[imida- zole-4,9′-xanthen]- 5(1H)-one and 418 A1 0.0136 1.97

(4S)-2-amino-4′- fluoro-7′-methoxy-1- methyl-2′-(4-methyl-phenyl)spiro[imida- zole-4,9′-xanthen]- 5(1H)-one 30

(4R)-2-amino-2′-(3,6- dihydro-2H-pyran-4- yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)- 3-pyridinyl)spiro [imidazole-4,9′-xanthen]-(5H)-one, 495 A2 0.0009 0.0137

(4S)-2-amino-2′-(3,6- dihydro-2H- pyran-4-yl)-4′-fluoro- 1-methyl-7′-(5-(1-propyn-1-yl)-3- pyridinyl)spiro [imidazole-4,9′- xanthen]-5(1H)-one31

(4R)-2-amino-2′-(3,6- dihydro-2H-pyran- 4-yl)-4′-fluoro- 1-methyl-7′-(5-(1-propyn-1-yl)-3- pyridinyl)spiro [imidazole-4,9′- xanthen]-5(1H)-one495 A2 0.179 4.41 32

(4S)-2-amino-2′- (3,6-dihydro-2H- pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1- propyn-1-yl)- 3-pyridinyl)spiro [imidazole-4,9′-xanthen]-5(1H)-one 495 A2 0.0005 0.0076 33

(4R)-2-amino-7′-(3- chlorophenyl)- 4′-fluoro-1-methyl-2′- (4-methyl-phenyl)spiro[imida- zole-4,9′-xanthen]- 5(1H)-one, 499 A2 0.0041 0.237

(4S)-2- amino-7′-(3- chlorophenyl)- 4′-fluoro-1- methyl-2′-(4-methyl-phenyl)spiro[imida- zole-4,9′-xanthen]- 5(1H)-one 34

(4S)-2-amino-7′-(3- chlorophenyl)-2′- (3,6-dihydro-2H-pyran-4-yl)-4′-fluoro- 1-methylspiro [imidazole-4,9′- xanthen]-5(1H)-one491 A2 0.0003 0.0099 35

(4R)-2-amino-7′-(3- chlorophenyl)-2′-(3,6- dihydro-2H-pyran-4-yl)-4′-fluoro-1- methylspiro [imidazole-4,9′- xanthen]-5(1H)-one 491 A20.0243 1.82 36

(4R)-2-amino-7′-(3- chlorophenyl)-4′- fluoro-1-methyl-2′- (4-methyl-phenyl)spiro[imida- zole-4,9′-xanthen]- 5(1H)-one 499 A2 0.225 >10 37

(4S)-2-amino-7′-(3- chlorophenyl)- 4′-fluoro-1-methyl-2′- (4-methyl-phenyl)spiro[imida- zole-4,9′-xanthen]- 5(1H)-one 499 A2 0.0029 0.147 38

(4R)-2-amino- 4′-fluoro-7′-(2-fluoro- 3-pyridinyl)-2′-2-fluoro-4-pyridinyl)- 1-methylspiro [imidazole-4,9′- xanthen]-5(1H)-one488 A2 0.169 0.29 39

(4S)-2-amino- 4′-fluoro-7′-(2-fluoro- 3-pyridinyl)-2′-(2-fluoro-4-pyridinyl)- 1-methylspiro [imidazole-4,9′- xanthen]-5(1H)-one488 A2 0.0002 0.0031 11

2′-amino-7-bromo-3- chloro-1-fluoro-1′- methyl-1′H- spiro[chromeno[2,3-c]pyridine-5,4′- pyrimidin]-6′(5′H)- one 424.9 427.0 Eg 11 + + 12

2′-amino-3-chloro-1- fluoro-7-(2- fluoropyridin-3-yl)-1′- methyl-1′H-spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)- one 442 Eg 12++ + 22

(S)-2′-amino-3-(3,6- dihydro-2H-pyran- 4-yl)-7-(2- fluoropyridin-3-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)-one 472.2 Eg 16 0.0093 0.0598 24

(S)-2′-amino-3-(5,6- dihydro-2H- pyran-3-yl)-7-(2- fluoropyridin-3-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)-one 472.2 Eg 16 0.0121 0.0523 23

(R)-2′-amino-3-(3,6- dihydro-2H-pyran-4- yl)-7-(2-fluoro- pyridin-3-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)-one 472.2 Eg 16 1.75 1.68 25

(R)-2′-amino-3-(5,6- dihydro-2H- pyran-3-yl)-7-(2- fluoropyridin-3-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)-one 472.2 Eg 16 2.43 6.17 21- A

(R)-2′-amino-7-(2- fluoropyridin-3-yl)- 3-(2-fluoropyridin- 4-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)- one485 Eg 16 0.437 2.38 21- B

(S)-2′-amino-7-(2- fluoropyridin-3-yl)- 3-(2-fluoropyridin- 4-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)- one485 Eg 16 0.0122 0.0995 18

2′-amino-1′-fluoro-7- (2-fluoropyridin- 3-yl)-3-(2-fluoropyridin-4-yl)-1′- methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′-pyrimidin]-6′(5′H)- one 503 Eg 16 0.0024 0.0716 16

2′-amino-3- (5,6-dihydro-2H- pyran-3-yl)-1-fluoro- 7-(2-fluoropyridin-3-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′-pyrimidin]-6′(5′H)- one 490 Eg 16 0.0014 0.0063 14

(R)-2′-amino-3- chloro-1-fluoro-7-(2- fluoropyridin-3-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridin-5,4′- pyrimidin]-6′(5′H)- one442 Eg 12 8.21 0.361 15

(S)-2′-amino-3- chloro-1-fluoro-7-(2- fluoropyridin-3-yl)-1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)-one 442 Eg 12 0.0332 0.643 19

(S)-2′-amino-1- fluoro-7-(2- fluoropyridin-3-yl)-3- (2-fluoropyridin-4-yl)-1′methyl-1′H- spiro[chromeno[2,3- c]pyridin-5,4′-pyrimidin]-6′(5′H)- one 503 Eg 16 0.0014 0.082 21

3,7-bis(2- fluoropyridin- 3-yl)-2′-imino-1′- methyl-2′,3′-dihydro-1′H-spiro(chromeno [2,3-c]pyridine-5,4′- pyrimidin]-6′(5′H)- one 485 Eg16 0.0483 0.426 20- A

(S)-7-bromo-3- chloro-2′- imino-1′-methyl- 2′,3′-dihydro-1′H-spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)- one 406.8 408.8Eg 10 + + 21- B

(R)-7-bromo- 3-chloro- 2′-imino-1′-methyl- 2′,3′-dihydro-1′H-spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)- one 406.8 408.8Eg 16 + + 17

(S)-2′-amino-3-(5,6- dihydro-2H-pyran-3- yl)-1-fluoro-7-(2-fluoropyridin-3-yl)- 1′-methyl-1′H- spiro[chromeno[2,3- c]pyridine-5,4′-pyrimidin]-6′(5′H)- one 490.1 Eg 16 0.0028 0.223 13

2′-amino-1-fluoro- 3,7-bis(2- fluoropyridin-3- yl)-1′-methyl-1′H-spiro[chromeno[2,3- c]pyridine-5,4′- pyrimidin]-6′(5′H)- one 503 Eg 130.0228 0.154 26

(S)-2′-amino-3-(6,6- dimethyl-3,6-dihydro- 2H-pyran-4-yl)-1-fluoro-7-(2- fluoropyriidn-3-yl)- 1′-methyl-1′H- spiro[chromeno[2,3-c]pyridine-5,4′- pyrimidin]-6′(5′H)- one 518.0 Eg 16 0.0006 0.005 27

(S)-2′-amino-3-(2,2- dimethyl-3,6-dihydro- 2H-pyran-4-yl)-1-fluoro-7-(2- fluoropyridin-3-yl)- 1′-methyl-1′H- spiro[chromeno[2,3-c]pyridine-5,4′- pyrimidin]-6′(5′H)- one 518.0 Eg 16 0.0007 0.005 28

(4′S)-2′-amino-3-(2,2- dimethyltetrahydro- 2H-pyran-4-yl)-1-fluoro-7-(2- fluoropyridin-3-yl)- 1′-methyl-1′H- spiro[chromeno[2,3-c]pyridin-5,4′- pyrimidin]-6′(5′H)- one 520.0 Eg 28 0.002 0.0022 40

N-(2-amino-2′- methoxy-1-methyl-5- oxo-1,5-dihydrospiro [imidazole-4,9′-xanthen]-7′-yl)- 5-chloropicolinamide 464 Eg. 40 0.0067 0.039

The following compounds in Table 2 are additional representativeexamples of Formulas I-III provided by the present invention.

TABLE 2

Ex. No. R² A³ A⁴ R⁷ W R⁹ 41 3,6-dihydro-2H-pyran- CH N2-Fluoropyridin-3-yl CH₂ CH₃ 3-yl 42 2,2-dimethyl- CH N2-Fluoropyridin-3-yl CH₂ C₂H₅ propanenitrile-oxyl 43 3-methyl-e-oxetane-CH CH 2-Fluoropyridin-3-yl absent CH₃ methoxyl 44 3-methyl-1H-pyrazolyl-CH CH 2-Fluoropyridn-3-yl absent C₂H₅ 45 3,6-dihydro-2H-pyran- CH N2-Fluoropyridin-3-yl CH₂ CH₃ 4-yl 46 2-F-pyrrolidin-1-yl CH N2-Fluoropyridn-3-yl CH₂ C₂H₅ 47 3,6-dihydro-2H-pyran-4- CH N2-Fluoropyridin-3-yl absent CH₃ yl 48 2,3-dimethyl-3,6-dihydro- CF N2-Fluoropyridin-3-yl absent C₂H₅ 2H-pyran-4-yl 49 3-methyl-3-oxetanyl-CF N 2-Fluoropyridin-3-yl CH₂ CH₃ ethynyl 50 3,6-dihydro-2H-pyran- CF N2-Fluoropyridin-3-yl CH₂ CH₃ 3-yl 51 2,2-dimethyl- CF N2-Fluoropyridin-3-yl CH₂ CH₃ propanenitrile-oxyl 52 3-methyl-3-oxetane-CF N 2-Fluoropyridin-3-yl CH₂ CH₃ methoxyl 53 3-methyl-1H-pyrazolyl- CFN 2-Fluoropyridin-3-yl absent CH₃ 54 3,6-dihydro-2H-pyran- CF N2-Fluoropyridin-3-yl absent C₂H₅ 4-yl 55 2-F-pyrrolidin-1-yl CF N2-Fluoropyridin-3-yl CH₂ CH₃ 56 3,6-dihydro-2H-pyran- CF N pyridin-3-ylCH₂ C₂H₅ 4-yl 57 2,3-dimethyl-3,6- CF N 2-Fluoropyridin-3-yl absent CH₃dihydro-2H-pyran-4-yl 58 3-methyl-3-oxetanyl- CF N 2-Fluoropyridin-3-ylabsent C₂H₅ ethynyl 59 3,6-dihydro-2H-pyran- CF N 2-Fluoropyridin-3-ylCH₂ CH₃ 3-yl 60 2,2-dimethyl- CF N 2-Fluoropyridin-3-yl CH₂ C₂H₅propanenitrile-oxyl 61 2-F-pyrrolidin-1-yl CH N 5-chloro-pyrazin-5- CH₂CH₃ yl-C(═O)—NH— 62 3,6-dihydro-2H-pyran- CF N 5-F-pyrazin-5-yl- CH₂ CH₃3-yl C(═O)—NH— 63 3-methyl-3-oxetane- CH N 5-chloro-pyrazin-5- absentCH₃ methoxyl yl-C(═O)—NH—

The present invention also provides methods for making compounds ofFormulas I-III, and sub-formulas therein. For example, the compounds inTable 2 and additional examples may be made by the following methods, assimilarly described in the literature references mentioned below.

In one embodiment of the invention, there is provided a method of makinga compound of Formula I, the method comprising the step of reacting acompound 20

wherein A¹, A³, A⁴, A⁵, A⁶, A⁸, R⁷, R⁹ and W of Formula I are as definedherein and halogen is either a bromine (Br) or chlorine (Cl), with acompound having the structure

or R²—B(OH)₂, wherein R² is as defined herein, to make a compound ofFormula I.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula II, the method comprising the step ofreacting a compound 20

wherein A¹, A³, A⁴, A⁵, A⁸, R⁷ and R⁹ of Formula II are as definedherein, with a compound having the structure

or R²—B(OH)₂, wherein R² is as defined herein, to make a compound ofFormula II.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula III, the method comprising the step ofreacting a compound 20

wherein A¹, A³, A⁴, R⁷, W, X, Y and Z of Formula III are as definedherein, with a compound having the structure

R²—B(OH)₂ or wherein R² is as defined herein, to make a compound ofFormula III.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula III-A, the method comprising the step ofreacting a compound 20

wherein A³, A⁴ and R⁷ of Formula III-A are as defined herein, with acompound having the structure

or R²—B(OH)₂, wherein R² is as defined herein, to make a compound ofFormula III-A.

As can be appreciated by the skilled artisan, the above syntheticschemes and representative examples are not intended to comprise acomprehensive list of all means by which the compounds described andclaimed in this application may be synthesized. Further methods will beevident to those of ordinary skill in the art. Additionally, the varioussynthetic steps described above may be performed in an alternatesequence or order to give the desired compounds.

For example, in these procedures, the steps may be preceded, orfollowed, by additional protection/deprotection steps as necessary.Particularly, if one or more functional groups, for example carboxy,hydroxy, amino, or mercapto groups, are or need to be protected inpreparing the compounds of the invention, because they are not intendedto take part in a specific reaction or chemical transformation, variousknown conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the inhibitorcompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) edition, John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); A. Katritzky and A.Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd) edition (2001); M.Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis,Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductionsby the Alumino- and Borohydrides in Organic Synthesis, 2^(nd) edition,Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

Salts, including pharmaceutically acceptable salts, of a compound of theinvention having a salt-forming group may be prepared in a conventionalmanner or manner known to persons skilled in the art. For example, acidaddition salts of compounds of the invention may be obtained bytreatment with an acid or with a suitable anion exchange reagent. A saltwith two acid molecules (for example a dihalogenide) may also beconverted into a salt with one acid molecule per compound (for example amonohalogenide); this may be done by heating to a melt, or for exampleby heating as a solid under a high vacuum at elevated temperature, forexample from 50° C. to 170° C., one molecule of the acid being expelledper molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplaryand suitable salts, and their preparation, are described herein in theDefinition section of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphaticethers, e.g., Et₂O and ethylene glycol dimethylether or cyclic ethers,e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene andxylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- andt-butanol; nitriles including CH₃CN; halogenated hydrocarbons, includingCH₂Cl₂, CHCl₃ and CCL; acid amides including DMF; sulfoxides, includingDMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine;carboxylic acids, including lower alkanecarboxylic acids, e.g., AcOH;inorganic acids including HCl, HBr, HF, H₂SO₄ and the like; carboxylicacid anhydrides, including lower alkane acid anhydrides, e.g., aceticanhydride; cyclic, linear, or branched hydrocarbons, includingcyclohexane, hexane, pentane, isopentane and the like, and mixtures ofthese solvents, such as purely organic solvent combinations, orwater-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

Purification methods are known in the art and include, for example,crystallization, chromatography (liquid and gas phase, and the like),extraction, distillation, trituration, reverse phase HPLC and the like.Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or generated in-situ and not isolated, prior to obtaining thefinally desired compound. Structures resulting from carrying out stepsfrom a transient starting material, structures resulting from divergencefrom the described method(s) at any stage, and structures formingstarting materials under the reaction conditions are all “intermediates”included in the invention. Further, structures produced by usingstarting materials in the form of a reactive derivative or salt, orproduced by a compound obtainable by means of the process according tothe invention and structures resulting from processing the compounds ofthe invention in situ are also within the scope of the invention.

The invention also provides new starting materials and/or intermediates,as well as processes for the preparation thereof. In select embodiments,such starting materials are used and reaction conditions so selected asto obtain the desired compound(s). Starting materials of the invention,are either known, commercially available, or can be synthesized inanalogy to or according to methods that are known in the art. Manystarting materials may be prepared according to known processes and, inparticular, can be prepared using processes described in the examples.In synthesizing starting materials, functional groups may be protectedwith suitable protecting groups when necessary. Protecting groups, theirintroduction and removal are described above.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. While shown without respect to stereochemistry inFormulas I-III, the present invention includes such optical isomers anddiastereomers, as well as the racemic and resolved, enantiomericallypure R and S stereoisomers, as well as other mixtures of R and Sstereoisomers and pharmaceutically acceptable salts thereof.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt. All such isomeric forms of such compounds areexpressly included in the present invention.

The compounds of the invention may also be represented in multipletautomeric forms. Tautomers often exist in equilibrium with each other,and interconvert under environmental and physiological conditions. Thecompounds of the invention may also occur in cis- or trans- or E- orZ-double bond isomeric forms. The invention expressly includes alltautomeric forms of the compounds described herein.

All crystal forms of the compounds described herein are expresslyincluded in the present invention.

The present invention also includes isotopically-labeled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H (deuterium), ³H(tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁶O, ¹⁷O, ³¹F, ³²F, ³⁵S, ¹⁸F, and ³⁶Cl.

Compounds of the present invention that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Deuterated (²H), Tritiated (³H) and carbon-14,i.e., ¹⁴C, isotopes are particularly preferred for their ease ofpreparation and detection. Further, substitution with heavier isotopessuch as deuterium, i.e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Isotopically labeled compounds of thisinvention can generally be prepared by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

Biological Evaluation

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Thepharmacokinetic and pharmacodynamic properties of a compound relate,directly and indirectly, to the ability of the compound to be effectivefor its intended use.

Although the pharmacological properties of the compounds of theinvention (Formulas I-III) vary with structural change, in general,activity possessed by compounds of Formulas I-III may be demonstratedboth in vitro as well as in vivo. The following exemplifiedpharmacological assays have been carried out with the compoundsaccording to the invention, to assess and characterize the compound'sability to modulate BACE activity and to regulate the cleavage ofamyloid beta precursor protein, thereby reducing or inhibiting theproduction of amyloid beta.

In Vitro Enzymatic BACE FRET (Fluorescence Resonance Energy Transfer)Assay (Enzyme Assay Data in the Example Table I)

The assay buffer used in this screen is 0.05 M acetate, pH 4.2, 10% DMSOfinal, 100 uM genapol (which is a nonionic detergent, below its CriticalMicelle Concentration). The Beta Secretase enzyme (0.2 nM) ispre-incubated for one hour with inhibitors, typically in about 1 uL ofDMSO according to a serial dilution, are added thereto. This assay iseffectively started by the addition of FRET substrate (50 nM) and thecombination is incubated for one hour. The FRET assay is terminated withby addition of Tris buffer, which raises the pH to neutrality, and thefluorescence is determined. The FRET substrate is a peptide withcommercially available fluorophore and quencher, on opposite sides ofthe BACE cleavage site. Proteolytic cleavage of the FRET substratereleases quenching of fluorescence (excitation 488 nm and emission 425nm).

Where available, the in-vitro BACE FRET enzyme data for each of theExamples is provided in Table I. Data key for the in-vitro BACE FRETassay is as follows:

“+” means the compound example has an IC₅₀ value of =to or >1.0 uM;

“++” means the compound example has an IC₅₀ value in the range from 100nM-1.0 uM (<1.0 uM to =or >100 nM);

“+++” means the compound example has an IC₅₀ value in the range from 25nM-100 nM (<100 nM to =or >25 nM); and

“++++” means the compound example has an IC₅₀ value in the range lessthan 25 nM (<0.1 uM).

In Vitro BACE Cell-Based Assay

The cell-based assay measures inhibition or reduction of Aβ40 inconditioned medium of test compound treated cells expressing amyloidprecursor protein.

Cells stably expressing Amyloid Precursor Protein (APP) were plated at adensity of 40K cells/well in 96 well plates (Costar). The cells werecultivated for 24 hours at 37° C. and 5% CO₂ in DMEM supplemented with10% FBS. The test compounds were then added to cells in 10-point doseresponse concentrations with the starting concentration being either 100μM or 10 μM. The compounds were diluted from stock solutions in DMSO andthe final DMSO concentration of the test compounds on cells was 0.1%.After 24 h of incubation with the test compounds the supernatantconditioned media was collected and the Aβ 40 levels were determinedusing a sandwich ELISA. The IC₅₀ of the compound was calculated from thepercent of control or percent inhibition of Aβ 40 as a function of theconcentration of the test compound.

The sandwich ELISA to detect Aβ 40 was performed in 96 well microtiterplates, which were pre-treated with goat anti-rabbit IgG (Pierce). Thecapture and detecting antibody pair that were used to detect Aβ 40 fromcell supernatants were affinity purified pAb40 (Biosource) andbiotinylated 6E10 (Signet Labs Inc.), respectively. The optimalconcentration for the pAb40 antibody was 3 μg/ml in Superblock/TBS(Pierce) that was supplemented with 0.05% Tween 20 (Sigma). Optimalconcentration for the detection antibody 6E10-biotinylated was 0.5 μg/mlin Superblock/TBS (Pierce) that had been supplemented with 2% normalgoat serum and 2% normal mouse serum.

Cellular supernatants were incubated with the capture antibody for 3 hat 4° C., followed by 3 wash steps in TBS-tween (0.05%). The detectingantibody incubation was for 2 h at 4° C., again followed by the washsteps as described previously. The final readout of the ELISA isTime-Resolved Fluorescence (counts per minute) using Delfia reagentsStreptavidin-Europium and Enhancement solutions (Perkin Elmer) and theVictor 2 multilabel counter (Perkin Elmer).

Where available, the in-vitro BACE cell based data for each of theExamples is provided in Table I. Data key for the in-vitro BACE cellbased assay is as follows:

“+” means the compound example has an IC₅₀ value of =to or >1.0 uM;

“++” means the compound example has an IC₅₀ value in the range from 100nM-1.0 uM (<1.0 uM to =or >100 nM);

“+++” means the compound example has an IC₅₀ value in the range from 25nM-100 nM (<100 nM to =or >25 nM); and

“++++” means the compound example has an IC₅₀ value in the range lessthan 25 nM (<0.1 uM).

In Vitro Enzymatic Cathepsin D (Cat D) FRET (Fluorescence ResonanceEnergy Transfer) Assay

Recombinant Cat D was expressed in CHO cells. The assay buffer forCathepsinD is 0.05 M citrate pH 3.5, 10% DMSO final, 5 mM CHAPS. The CatD enzyme (9 nM) is pre-incubated for one hour with inhibitors, typicallyin about luL of DMSO according to a serial dilution, is added thereto.The assays are effectively started by the addition of different FRETsubstrates (20 nM for Cat D) and the combination is incubated for onehour. The FRET assay is terminated with by addition of Tris buffer,which raises the pH to neutrality, and the fluorescence is determined.The FRET substrate is a peptide with commercially available fluorophoreand quencher, on opposite sides of the BACE cleavage site. The Cat Dsubstrate peptide sequence is based on sequence #1 of Table 1 fromGulnik et al. FEB S Letters v413 p 379-384 1997. Proteolytic cleavage ofthe FRET substrate releases quenching of fluorescence (Cat D excitation500 nm and emission 580 nm).

Alternatively, a Cat D assay may also be run according to the proceduredescribed in the article, Characterization of new fluorgenic substratesfor the rapid and sensitive assay of cathepsin E and cathepsin D, J.Biochem., 125:1137, 1999. In addition, the cathepsin D and cathepsin Eassays are described in PCT publication WO2011069934. This WIPOpublication describes BACE inhibitor compounds having an amide linkerconnecting two aromatic groups with extremely poor cathepsin D and/orcathepsin E inhibitory activity (see Table 2).

Where available, the in-vitro Cat D FRET assay data for each of theExamples, conducted by the first procedure, is provided. For example,the compoundof example 40 has a Cat D IC₅₀ value of 7.4 uM. As shown bythe high micromolar Cat D data (very poorly active or inactive againstcat D), the compounds of the present invention possess the unexpectedproperty of little to no ability to inhibit the activity of Cat D. Itwas surprisingly found that incorporation of a linker “L” between thecore of the compounds and the R⁷ group has conferred a significantlyreduced, poor or no potency on the protein Cat D. Thus, with thissurprising selectivity profile, the compounds of the present inventionare believed to minimize, reduce or completely eliminate any risk ofretinal atrophy and abnormal development of the eye and of the retinalpigmented epithelium as it relates to the normal function and activityof Cat D.

In vivo Inhibition of Beta-Secretase

Several animal models, including mouse, rat, dog, and monkey, may beused to screen for inhibition of beta-secretase activity in vivofollowing administration of a test compound sample. Animals used in thisinvention can be wild type, transgenic, or gene knockout animals. Forexample, the Tg2576 mouse model, prepared and conducted as described inHsiao et al., 1996, Science 274, 99-102, and other non-transgenic orgene knockout animals are useful to analyze in vivo inhibition ofAmyloid beta peptide (Abeta) production in the presence of inhibitorytest compounds. Generally, 2 to 18 month old Tg2576 mice, gene knockoutmice or non-transgenic animals are administered test compoundsformulated in vehicles, such as cyclodextran, phosphate buffers,hydroxypropyl methylcellulose or other suitable vehicles. One totwenty-four hours following the administration of compound, animals aresacrificed, and brains as well as cerebrospinal fluid (CSF) and plasmaare removed for analysis of A-beta levels and drug or test compoundconcentrations (Dovey et al., 2001, Journal of Neurochemistry, 76,173-181) Beginning at time 0, animals are administered by oral gavage,or other means of delivery such as intravenous injection, an inhibitorytest compound of up to 100 mg/kg in a standard, conventionalformulation, such as 2% hydroxypropyl methylcellulose, 1% Tween80. Aseparate group of animals receive 2% hydroxypropyl methylcellulose, 1%Tween80 alone, containing no test compound, and serve as avehicle-control group. At the end of the test period, animals aresacrificed and brain tissues, plasma or cerebrospinal fluid arecollected. Brains are either homogenized in 10 volumes (w/v) of 0.2%diethylamine (DEA) in 50 mM NaCl (Best et al., 2005, Journal ofPharmacology and Experimental Therapeutics, 313, 902-908), or in 10volumes of 0.5% TritonX-100 in Tris-buffered saline (pH at about 7.6).Homogenates are centrifuged at 355,000 g, 4° C. for 30 minutes. CSF orbrain supernatants are then analyzed for the presence of A-beta peptideby specific sandwich ELISA assays based on ECL(Electrochemiluminescence) technology. For example, rat Abeta40 ismeasured using biotinylated-4G8 (Signet) as a capture antibody and Fab40(an in-house antibody specific to the C-terminal of Abeta40) as adetection antibody. For example, 4 hours after administration of 30mg/kg oral dose of the test compound in 2% hydroxypropylmethylcellulose, 1% Tween80 (pH2.2) to 200 g male Sprague Dawley rats,amyloid beta peptide levels are measured for reduction by X % and Y % incerebrospinal fluid and brain, respectively, when compared to the levelsmeasured in the vehicle-treated or control mice.

Actual vehicles used: Oral: 2% HPMC, 1% Tween80, pH 2.2

-   -   IV: 5% EtOH, 45% Propylene glycol in 5% Dextrose

The compounds of the invention may be shown to reduce the formationand/or deposition of amyloid beta peptide in the cerebrospinal fluid(CSF) as well as in the brain of a mouse or rat at both 10 mpk (mpk=mgcompound per kg animal) and 30 mpk dosing concentrations after 41 hrs.

Indications

According to the amyloid cascade hypothesis, cerebral deposition ofamyloid-beta peptide (Aβ) is critical for Alzheimer's disease (AD)pathogenesis. Aβ generation is initiated when β-secretase (BACE1)cleaves the amyloid precursor protein. De Meyer et al re-affirm thebelieved role which the accumulation of beta-amyloid protein (A-beta) incerebral spinal fluid (CSF) in a subject plays in the progression ofsymptoms, initially revealed as mild cognitive impairment, whichultimately leads to AD. Arch Neurol. 67(8):949-956, 2010. Amyloid-b (Ab)peptides generated from amyloid precursor protein (APP) by proteolyticcleavage, such as by aspartyl protease enzymes including beta-secreatase(BACE) and gamma-secretase, likely play a causal role in AD pathogenesis(Tanzi and Bertram, Cell, (120): 545-555, 2005; Walsh and Selkoe,Neuron, (44): 181-193, 2004). Although the precise mechanisms of Abtoxicity are unclear, oligomeric forms of Ab may contribute to cognitivedecline by altering synaptic structure and function (Palop and Mucke,Nat. Neuroscience, (13): 812-818, 2010; Selkoe, Behavioral Brain Res.,(192): 106-113, 2008; Shankar et al., Nat. Medicine (14): 837-842,2008). Transgenic mouse models that overexpress mutant APP and producehigh levels of Ab show amyloid plaque deposition, synaptic deficits,learning and memory impairments, and other behavioral abnormalities(Games et al., Nature, (373): 523-527, 1995; tz et al., MolecularPsychiatry (9): 664-683, 2004; Hsia et al., Proc. Natl. Academy ofScience USA (96): 3228-3233, 1999; Hsiao et al., Science (274): 99-102,1996, citing Harris et al, Neuron (68): 428-441, 2010).

For more than a decade, BACE1 has been a prime target for designingdrugs to prevent or treat AD. However, development of such agents hasturned out to be extremely challenging, with major hurdles in cellpenetration, oral bioavailability/metabolic clearance, and brain access.

Bapineuzamab, a monoclonal amino-terminus specific anti-amyloid antibodyis presently in Phase III clinical trials for the treatment of AD.Alzheimer's Research & Therapy, 1:2, 2009. Each of the known geneticcauses of AD is linked to A-beta. Dementia, Down's Syndrome to APPover-production, are all believed to be linked to the deposition ofA-beta on the brain. With methods for identifying brain amyloiddeposition, positron emission scanning (PET) and CSF measurements ofAb42, identification of AD suffering individuals needing treatment isbecoming easier amd more common It is firmly believed that by reducingthe formation of A-beta, one can begin to pre-treat AD. Vassar et al,Journal of Neuroscience, 29 (41):12787-12794, 2009. One publishedpathway for treatment of AD is inhibition of beta-secretase. Tirrell,Bloomberg News, The Boston Globe, Jan. 7, 2010.

The US biotech company CoMentis is developing an orally bioavailablesmall molecule CTS-21166, a highly potent, highly selective andefficacious brain-penetrating beta-secretase inhibitor. CoMentissuccessfully completed a Phase I study of CTS-21166 in healthyvolunteers in 2008. Results indicated that CTS-21166 was safe,well-tolerated and pharmacodynamically active at all dose levels. Allclinical subjects administered CTS-21166 showed area-under-curve (AUC)reduction in plasma A-Beta40 reductions ranging from 40-75%. Because ofthe urgent need for AD treatment, Phase II studies for CTS-2166 areplanned, or ongoing, for AD patients. In preclinical studies, CTS-21166exhibits excellent efficacy, selectivity, brain penetration andpharmacologic activity.

Using afragment-based chemistry strategy, Eli Lilly and companygenerated LY2811376[(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine],an orally available non-peptidic BACE1 inhibitor that produces profoundAβ-lowering effects in animals. The biomarker changes obtained inpreclinical animal models translate into man at doses of LY2811376 thatwere safe and well tolerated in healthy volunteers (US Ph I Clinicaltrial—www.clinicaltrials.gov). Prominent and long-lasting Aβ reductionsin lumbar CSF were measured after oral dosing of 30 or 90 mg ofLY2811376. This represents the first translation of BACE1-drivenbiomarker changes in CNS from preclinical animal models to man. Becauseof toxicology findings identified in longer-term preclinical studies,this compound is no longer progressing in clinical development. However,BACE1 remains a viable target because the adverse effects reported herewere recapitulated in LY2811376-treated BACE1 KO mice and thus areunrelated to BACE1 inhibition. The magnitude and duration of central Af3reduction obtainable with BACE1 inhibition positions this protease as atractable small-molecule target through which to test the amyloidhypothesis in man. Neuroscience, 31(46):16507-16515, 2011

The compounds of the invention have been shown to modulate, andspecifically inhibit the activity of the beta-secretase enzyme, therebyreducing the A-beta peptide fragments. Accordingly, compounds of theinvention are useful for, but not limited to, the prevention ortreatment of beta-secretase related diseases, including Alzheimer'sdisease. The compounds of the invention have the ability to modulate theactivity of beta secretase enzyme, thereby regulating the production ofamyloid beta (Abeta peptide) and reducing the formation and depositionof Abeta peptide in both the cerebral spinal fluid as well as in thebrain, resulting in a decrease of amyloid plaque on the brain. In oneembodiment of the invention, there is provided a method of treating adisorder related to a beta-secretase enzyme in a subject, the methodcomprising administering to the subject an effective dosage amount of acompound of Formulas I, II, III, and sub-formulae thereof. In anotherembodiment, there is provided a method of reducing production of amyloidbeta, and of reducing plaque formation on the brain. In anotherembodiment, there is provided a method for the treatment, prevention oramelioration of a disease or disorder characterized by the elevatedbeta-amyloid deposits or beta-amyloid levels in a subject, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound according to any of Formulas I-III. In yet anotherembodiment, the invention provides a method of treating Alzheimer'sdisease, cognitive impairment including mild, moderate and/or severe,Down's Syndrome, cognitive decline, senile dementia, cerebral amyloidangiopathy or a neurodegenerative disorder.

Accordingly, the compounds of the invention would be useful in therapyas CNS agents in treating neurological disorders and related conditionsin subjects.

In one embodiment, the compounds of the invention are provided for themanufacture of a medicament, or a pharmaceutical composition, for thetherapeutic and/or prophylactic treatment of diseases and disorderscharacterized by elevated levels of β-amyloid and/or β-amyloid oligomersand/or b-amyloid plaques and further deposits, including Alzheimer'sDisease. In another embodiment, the invention provides compounds, ineffective dosage amounts, for the therapeutic and/or prophylactictreatment of AD. Thus, the compounds of the invention may be used totreat prodromol patients, i.e., subjects exhibiting the biomarkersand/or hallmarks of developing AD.

Besides being useful for human treatment, the compounds of the inventionmay be useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Forexample, animals including horses, dogs, and cats may be treated withcompounds provided herein.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating neurological disorders and beta-secretase mediateddiseases with the compounds and/or compositions of this inventiondepends on a variety of factors, including the age, weight, sex andmedical condition of the subject, the type of disease, the severity ofthe disease, the route and frequency of administration, and theparticular compound employed. Thus, the dosage regimen may vary widely,but can be determined routinely using standard methods. A daily dose ofabout 0.01 to 500 mg/kg, advantageously between about 0.01 and about 50mg/kg, more advantageously about 0.01 and about 30 mg/kg, and even moreadvantageously between about 0.1 and about 10 mg/kg body weight may beappropriate, and should be useful for all methods of use disclosedherein. The daily dose can be administered in one to four doses per day.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered normally willbe present as an active ingredient in a pharmaceutical composition.Thus, in another embodiment of the invention, there is provided apharmaceutical composition comprising a compound of this invention incombination with a pharmaceutically acceptable excipient, which includesdiluents, carriers, adjuvants and the like (collectively referred toherein as “excipient” materials) as described herein, and, if desired,other active ingredients. A pharmaceutical composition of the inventionmay comprise an “effective amount” of a compound of the invention or an“effective dosage amount” of a compound of the invention. An “effectivedosage amount” of a compound of the invention includes an amount lessthan, equal to or greater than an effective amount of the compound. Forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound is administered byadministering a portion of the composition.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,advantageously from about 1 to 500 mg, and typically from about 5 to 150mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods and practices.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or other “excipients”appropriate to the indicated route of administration. If orallyadministered on a per dose basis, the compounds may be admixed withlactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, to form the final formulation. For example,the active compound(s) and excipient(s) may be tableted or encapsulatedby known and accepted methods for convenient administration. Examples ofsuitable formulations include, without limitation, pills, tablets, softand hard-shell gel capsules, troches, orally-dissolvable forms anddelayed or controlled-release formulations thereof. Particularly,capsule or tablet formulations may contain one or morecontrolled-release agents, such as hydroxypropylmethyl cellulose, as adispersion with the active compound(s).

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, and preferably from about 0.1 to about 10mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.Accordingly, in yet another embodiment of the present invention, thereis provided a method of manufacturing a medicament, the methodcomprising combining an amount of a compound according to Formulas I-IIIwith a pharmaceutically acceptable carrier to manufacture themedicament.

In yet another embodiment, the invention provides a method ofmanufacturing a medicament for the treatment of Alzheimer's disease, themethod comprising combining an amount of a compound according toFormulas I-III with a pharmaceutically acceptable carrier to manufacturethe medicament.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of beta-secretase,gamma-secretase and/or other reagents known in influence the formationand/or deposition of amyloid beta, otherwise responsible for theformation of plaque on the brain.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I, II and III may also be administered sequentially withother known medicinal agents. The invention is not limited in thesequence of administration; compounds of the invention may beadministered either prior to, simultaneous with or after administrationof the known anti-inflammatory agent.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

What is claimed is:
 1. A compound of Formula I:

or a stereoisomer, tautomer, hydrate, solvate or pharmaceuticallyacceptable salt thereof, wherein A¹ is CR¹ or N; A³ is CR³ or N; A⁴ isCR⁴ or N; A⁵ is CR⁵ or N; A⁶ is CR⁶ or N; A⁸ is CR⁸ or N, provided thatno more than one of A¹, A³, A⁴, A⁵, A⁶ and A⁸ is N; L is absent or L is—C(═O)NH—, —C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—; each of R¹, R⁴, R⁵ andR⁸, independently, is H, F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH,—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl,wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; R² is Cl, Br,C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃)₃, whereinthe C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl and C₃₋₆cycloalkyl are optionallysubstituted, independently, with 1-5 substituents of R¹⁰; each of R³ andR⁶, independently, is H, halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN,OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl; R⁷is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —SC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰; R⁹ is H, C₁₋₆-alkyl, CN,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl or benzyl, whereinthe C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; each R¹⁰,independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, —C(O)NHCH₃,oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl; W is absent, CH₂ or CF₂; and Y is —C(═O)—or —SO₂—.
 2. The compound of claim 1 having a Formula I-A:

or a stereoisomer, tautomer, hydrate, solvate or pharmaceuticallyacceptable salt thereof, wherein A¹ is CR¹ or N; A³ is CR³ or N; A⁴ isCR⁴ or N; A⁵ is CR⁵ or N; A⁶ is CR⁶ or N; A⁸ is CR⁸ or N, provided thatno more than one of A¹, A³, A⁴, A⁵, A⁶ and A⁸ is N; each of R¹, R⁴, R⁵and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH,—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl,wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; R² is Cl, Br,C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R¹⁰;each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl; R⁷ is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl,—NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰; R⁹ is H, C₁₋₆-alkyl, CN,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl or benzyl, whereinthe C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; each R¹⁰,independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, —C(O)NHCH₃,oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl; and W is absent or CH₂.
 3. The compound ofclaim 1, or a stereoisomer, tautomer or pharmaceutically acceptable saltthereof, wherein A^(l) is CH or CF; A³ is CH, CF or N; A⁴ is CH, CF orN; A⁵ is CH, CF or N; A⁶ is CH, CF or N; A⁸ is CH or CF; and R⁹ is CH₃,C₂H₅, propyl, butyl, acetyl or benzyl.
 4. The compound of claim 1, or astereoisomer or pharmaceutically acceptable salt thereof, wherein eachof R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, CF₃, OCF₃, methyl,ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃; one of R² and R⁷,independently, is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza -[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or -Si(CH₃) ₃, wherein the phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza -bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-3 substituents of R¹⁰; theother of R² and R⁷, independently, is C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl or —NH-benzyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂,—NH-phenyl and —NH-benzyl are optionally substituted, independently,with 1-3 substituents of R¹⁰; each of R³ and R⁶, independently, is H,halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,SC₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl; and R⁹ is CH₃ or benzyl. 5.The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R⁷ is a ring selected from phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,thiazolyl, thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, said ringoptionally substituted, independently, with 1-3 substituents of R¹⁰ . 6.The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R² is halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or a ring selected from phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,thiazolyl, thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R¹⁰; each of R¹,R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH; each of R³ andR⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH, OCH₃, SCH₃ orNHCH₃; R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, triazinyl or thienyl, said ring optionallysubstituted, independently, with 1-3 substituents of R¹⁰; and R⁹ is CH₃.7. The compound of claim 1, or a stereoisomer, tautomer, hydrate,solvate or pharmaceutically acceptable salt thereof, having a Formula II

wherein A^(l) is CR¹ or N; A³ is CR³ or N; A⁴ is CR⁴ or N; A⁵ is CR⁵ orN; A⁶ is CR⁶ or N; A⁸ is CR⁸ or N, provided that no more than one of A¹,A³, A⁴, A⁵, A⁶ and A⁸ is N; L is absent or L is —C(═O)NH—,—C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—; each of R¹, R⁴, R⁵ and R⁸,independently, is H, F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH,—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl,wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; R² is Cl, Br,C₁₋₆-alkyl, C₂₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃) ₃, whereinthe C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, and C₃₋₆cycloalkyl are optionallysubstituted, independently, with 1-5 substituents of R¹⁰; each of R³ andR⁶, independently, is H, halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN,OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl; R⁷is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza -[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R¹⁰; R⁹is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portionof —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and -C(O)C₁₋₆-alkylare optionally substituted with 1-3 substituents of F, oxo or OH; andeach R¹⁰, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁ ₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl; and Y is —C(═O)— or —SO₂—.
 8. The compoundof claim 7, or a stereoisomer, tautomer, hydrate, solvate orpharmaceutically acceptable salt thereof, having a Formula II-A

wherein A^(l) is CR¹ or N; A³ is CR³ or N; A⁴ is CR⁴ or N; A⁵ is CR⁵ orN; A⁶ is CR⁶ or N; A⁸ is CR⁸ or N, provided that no more than one of A¹,A³, A⁴, A⁵, A⁶ and A⁸ is N; each of R¹, R⁴, R⁵ and R⁸, independently, isH, F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)₀C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH; R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or -Si(CH₃) ₃,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza -[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R¹⁰;each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)₀C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl; R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl,—NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza -[3,5]-spironon-7-yl,cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza -[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R¹⁰; R⁹ is H, C₁₋₆-alkyl, CN,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl or benzyl, whereinthe C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; and each R¹⁰,independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, —C(O)NHCH₃,oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, morpholinyl, pyrazolyl,isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, isoptionally substituted independently with 1-5 substituents of F, Cl, CN,NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃thioalkoxyl, or oxetanyl.
 9. The compound of claim7, or a stereoisomer or pharmaceutically acceptable salt thereof,wherein A^(l) is CR¹; A³ is CR³ or N; A⁴ is CR⁴ or N; A⁵ is CR⁵; A⁶ isCR⁶; A⁸ is CR⁸; each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl,CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃; one ofR² and R⁷, independently, is phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza -[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or -Si(CH₃) ₃,wherein the phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza -[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-3 substituents of R⁹; theother of R² and R⁷, independently, is C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkynyl, —NHC₁₋₆alkynyl,—N(C₁₋₃alkyl)₂, —NH-phenyl or —NH-benzyl, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkynyl,—N(C₁₋₃alkyl)₂, —NH-phenyl and —NH-benzyl are optionally substituted,independently, with 1-3 substituents of R⁹; each of R³ and R⁶,independently, is H, halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH,OC₁₋₆-alkyl, SC₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl; and R⁹ is CH₃,C₂H₅, propyl, butyl, acetyl or benzyl.
 10. The compound claim 9, or astereoisomer or pharmaceutically acceptable salt thereof, wherein A³ isCR³ or N; A⁴ is CR⁴; R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ringare optionally substituted, independently, with 1-3 substituents of R¹⁰;each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃; R⁷ is a ring selected from phenyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, triazinyl or thienyl, said ringoptionally substituted, independently, with 1-3 substituents of R¹⁰; andR⁹ is CH₃.
 11. The compound of claim 1, or a stereoisomer, tautomer,hydrate, solvate or pharmaceutically acceptable salt thereof, having aFormula III

wherein A^(l) is CR¹ or N; A³ is CR³ or N; A⁴ is CR⁴ or N; A⁵ is CR⁵ orN; A⁶ is CR⁶ or N; A⁸ is CR⁸ or N, provided that no more than one of A¹,A³, A⁴, A⁵, A⁶ and A⁸ is N; L is absent or L is —C(═O)NH—,—C(═O)N(CH₃)—, —NH—, —N(CH₃)— or —O—; each of R¹, R⁴, R⁵ and R⁸,independently, is H, F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH,—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl,wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)₀C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; R² is Cl, Br,C₁₋₆-alkyl, C₂₄alkenyl, C₂₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃) ₃, whereinthe C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl, andC₃₋₆cycloalkyl are optionally substituted, independently, with 1-5substituents of R10; each of R³ and R⁶, independently, is H, halo,haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl; R⁷ is C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza[3,5]-spironon-7-yl, cyclopentyland cyclohexyl are optionally substituted, independently, with 1-5substituents of R¹⁰; R⁹ is H, C₁₋₆-alkyl, CN, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl, —C(O)C₁₋₆-alkyl or benzyl, wherein the C₁₋₆-alkyl andC₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyland —C(O)C₁₋₆-alkyl are optionally substituted with 1-3 substituents ofF, oxo or OH; and each R¹⁰, independently, is halo, haloalkyl, CN, OH,NO₂, NH₂, acetyl, —C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl,C₁₋₆thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl ordioxolyl, wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl,C₁₋₆thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,pyrrolidinyl, oxetanyl or dioxolyl, is optionally substitutedindependently with 1-5 substituents of F, Cl, CN, NO₂, NH₂, OH, oxo,methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃dialkylamino, C₁₋₃thioalkoxyl, or oxetanyl.
 12. Thecompound of claim 11, or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein A^(l) is CR¹; A³ is CR³ or N; A⁴ is CR⁴ or N; A⁵is CR⁵; A⁶ is CR⁶; A⁸ is CR⁸; L is —C(═O)NH—, —C(═O)N(CH₃)—, —NH—,—N(CH₃)—or —O—; each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl,CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃; one ofR² and R⁷, independently, is phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, thienyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza -[3,5 ]-spironon-7-yl, C₃₋₆cycloalkyl or —Si(CH₃)₃, whereinthe phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, thienyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza -bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl and C₃ ₋₆cycloalkyl are optionallysubstituted, independently, with 1-3 substituents of R⁹; the other of R²and R⁷, independently, is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₃₋₆cycloalkyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl or —NH-benzyl, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄allcynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl and —NH-benzyl are optionally substituted,independently, with 1-3 substituents of R⁹; each of R³ and R⁶,independently, is H, halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH,OC₁₋₆-alkyl, SC₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl; and R⁹ is CH₃,C₂H₅, propyl, butyl, acetyl or benzyl.
 13. The compound of claim 11, ora stereoisomer or pharmaceutically acceptable salt thereof, wherein A³is CR³ or N; A⁴ is CR⁴; L is —C(═O)NH—; R² is halo, haloalkyl,haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or a ring selectedfrom phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ringare optionally substituted, independently, with 1-3 substituents of R¹⁰;each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃; R⁷ is a ring selected from phenyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, triazinyl or thienyl, said ringoptionally substituted, independently, with 1-3 substituents of R¹⁰; andR⁹ is CH₃.
 14. The compound of claim 1, or a stereoisomer orpharmaceutically acceptable salt thereof, selected from(4R)-2-amino-2′-methoxy-1-methyl-7′-(5-pyrimidinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one,(4S)-2-amino-2′-methoxy-1-methyl-7′-(5-pyrimidinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoro-3-pyridinyl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoro-3-pyridinyl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-4′-fluoro-7′-methoxy-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4S)-2-amino-4′-fluoro-7′-methoxy-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4S)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4S)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methyl-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4S)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4S)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4S)-2-amino-7′-(3-chlorophenyl)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-7′-(3-chlorophenyl)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4S)-2-amino-7′-(3-chlorophenyl)-4′-fluoro-1-methyl-2′-(4-methylphenyl)spiro[imidazole-4,9′-xanthen]-5(1H)-one;(4R)-2-amino-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-fluoro-4-pyridinyl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one; and(4S)-2-amino-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-fluoro-4-pyridinyl)-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one; andN-(2-amino-2′-methoxy-1-methyl-5-oxo-1,5-dihydrospiro[imidazole-4,9′-xanthen]-7′-yl)-5-chloropicolinamide.15. The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, selected from2′-amino-7-bromo-3-chloro-1-fluoro-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(R)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(R)-2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(R)-2′-amino-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-2′-amino-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;2′-amino-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(R)-2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-2′-amino-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-2′-amino-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;3,7-bis(2-fluoropyridin-3-yl)-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-7-bromo-3-chloro-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(R)-7-bromo-3-chloro-2′-imino-1′-methyl-2′,3′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;2′-amino-1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-2′-amino-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;(S)-2′-amino-3-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one;and(4′S)-2′-amino-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one.16. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.
 17. A method oftreating Alzheimer's disease, cognitive impairment or a combinationthereof in a subject, the method comprising administering to the subjectan effective dosage amount of the compound of claim
 1. 18. A method oftreating a neurological disorder selected from the group consisting ofmild cognitive impairment, Down's syndrome, Hereditary cerebralhemorrhage with dutch-type amyloidosis, cerebral amyloid angiopathy,degenerative dementia, dementia associated with Parkinson's disease,dementia associated with supranuclear palsy, dementia associated withcortical basal degeneration, diffuse lewy body type of Alzheimer'sdisease or a combination thereof in a subject, the method comprisingadministering to the subject an effective dosage amount of the compoundof claim
 1. 19. A process for preparing a compound of claim 1, theprocess comprising the step of reacting a compound 20

wherein A¹, A³, A⁴, A⁵, A⁶, A⁸, R², R⁹ and W of compound 20 are asdefined in claim 1 and X is NH₂, Cl or Br, with a compound having thestructure

R⁷—B(OH)₂ or R⁷—C(═O)Cl wherein R⁷ is as defined in claim 1.